Explore how GPCR signaling shapes mosquito feeding and mating behaviors with Dr. Laura Duvall. Insights for GPCR researchers and functional assay innovators. << Back to podcast list Strategic Partner(s) Why Mosquitoes Hunt You: GPCR Control of Blood Feeding and Mating Scientific Abstract A female mosquito that has just fed on human blood stops seeking humans for three to four days while she digests that meal and develops eggs. Laura Duvall's lab has traced this suppression to a specific neuropeptide Y family receptor, one she first identified as a postdoctoral fellow and has since found expressed almost exclusively in an unexpected tissue, the mosquito rectum. Her group works at the intersection of neuropeptide signaling, behavioral genetics, and vector biology in Aedes aegypti, the species responsible for transmitting Zika, dengue, and chikungunya. This conversation traces her path from circadian rhythm research in Drosophila to mosquito behavior, and lays out why a receptor built to regulate host seeking and mating might offer a way to interrupt pathogen transmission at its source rather than treating each disease separately. What pulls Duvall back to this receptor personally is its apparent conservation: the same NPY family receptor she found in mosquito gut tissue has a close relative in the human colon, doing a job no one has fully worked out yet. About Laura Duvall runs a research lab in the Department of Biological Sciences at Columbia University, where her group studies how mosquitoes regulate innate behaviors, primarily blood feeding and mating. She trained in neuroscience during her PhD, characterizing how pigment dispersing factor and related GPCRs coordinate circadian clock cells in the Drosophila brain, then moved into mosquito research as a postdoctoral fellow with Leslie Vosshall at Rockefeller University. Her lab uses CRISPR based gene editing, automated behavioral assays, and video tracking to study neuropeptide Y family receptors in Aedes aegypti, with a particular focus on host seeking suppression and female mating receptivity. Scientific Themes of the Conversation - Neuropeptide Y family receptors as conserved regulators of feeding and reproductive behavior - Host seeking suppression in blood fed females as a druggable behavioral switch - Cross species pharmacological crosstalk between human and mosquito receptors - Unexpected receptor localization outside canonical neuronal tissue - Automated, experimenter free behavioral assays as a response to human bias in the data - Vector behavior disruption as an alternative to pathogen specific therapeutics Key Insights from the Conversation A single gene deletion reopened a closed behavioral window. Duvall's lab used CRISPR to mutate the receptor she had identified as important for host seeking suppression. Blood fed females that should have lost interest in humans for several days continued seeking hosts anyway. Watching one gene override such a strong, evolutionarily tuned behavioral drive was, in her words, almost magical. A neuropeptide receptor turned up in a tissue no one expected. When the lab went looking for where this NPY family receptor was expressed, they assumed brain tissue. Instead, expression was almost exclusive to the mosquito rectum, a structure Duvall says she did not know existed as a distinct entity until the result came back. The rectal finding stopped looking strange once the mammalian literature caught up. Humans and other mammals have NPY2 receptors in the colon, and non-neuronal excitable cells there are known to synthesize and release neurotransmitters. Work on neuropod and enterochromaffin cells in mammals has become a guide for what Duvall's lab looks for next in the mosquito gut. Removing the experimenter from the room removed a source of bias. Duvall's team built an automated system to deliver host associated cues to mosquitoes around the clock, including at 4am and in darkness, specifically because a human presence, and even which human is present, measurably skews mosquito attraction data. Baseline attractiveness to mosquitoes is real, stable, and not about soap. Referencing work from a former labmate, Duvall described how a person's attractiveness to mosquitoes stays consistent over time regardless of shampoo or soap, which is why her lab has to control carefully for who serves as the human stimulus in an assay. One receptor sits at the intersection of two very different behaviors. The same NPY family Duvall calls her favorite includes a receptor in the female mosquito that detects a male derived signal after mating and suppresses her receptivity to mate again, sometimes for the rest of her life. Disrupting it experimentally can leave females able to mate with multiple males. Disrupting one behavior could interrupt transmission of several diseases at once. Because Aedes aegypti transmits Zika, dengue, and chikungunya through the same host seeking behavior, Duvall argues that turning off attraction to humans at the level of the receptor could block all of these pathogens at their point of transmission, rather than requiring a therapeutic for each one. Episode Timeline - Growing up in rural North Carolina, where the path to science ran through a work study job in a lab - Choosing neuroscience and circadian rhythms as a graduate research focus - Studying pigment dispersing factor signaling in Drosophila clock cells, and a first entry point into GPCRs - An interview that turned into a mosquito postdoc with Leslie Vosshall - Identifying a neuropeptide Y family receptor important for blood feeding regulation - A CRISPR edit that reopened host seeking behavior in blood fed females - What CRISPR based mosquito gene editing looks like in practice, from guide design to the olfactometer assay - Moving to automated, video tracked behavioral assays to remove human bias from the data - Finding the receptor expressed almost exclusively in the mosquito rectum, and its parallel in the human colon - Disrupting host seeking behavior as a way to block transmission of Zika, dengue, and chikungunya - Building a mosquito research facility from scratch, and what day to day lab life looks like - The receptor behind mating suppression in female mosquitoes, and its favorite status in the lab Timestamps were generated using AI for readability. Selected Quotes "This mutant mosquito disrupting a single gene and changing this incredibly strong behavioral drive was something that was almost magical." "It's a neuropeptide receptor, but in fact it seems to be expressed exclusively in the mosquito rectum. A tissue that I did not know existed until we got this result." "There's nothing more satisfying than just sticking your arm in a tube and seeing if you can get them to turn down their attraction to your arm." "In some ways my view of neuroscience and signaling between the brain and the body is relatively narrow. It's really important to have these sensors everywhere in the system." Guest Links - LinkedIn: https://www.linkedin.com/in/laura-duvall-28a03485/ - Google Scholar: https://scholar.google.com/citations?user=Vk3KGSoAAAAJ&hl=en - Lab: https://www.duvalllab.com/ Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. Foord reflects on discovering RAMPs, deorphanizing GPCRs, and navigating industrial GPCR pharmacology, target validation, and drug discovery strategy. << Back to podcast list Strategic Partner(s) Foord: Serendipity, RAMPs, And Industrial GPCR Pharmacology Scientific Abstract This conversation traces how GPCR pharmacology, receptor signaling, and drug discovery evolved inside one of the world’s largest pharmaceutical organizations. Dr. Foord reflects on his path from academic neuroendocrinology to introducing molecular biology and molecular pharmacology into Glaxo’s GPCR programs, and on the combination of rigor, bioinformatics, and serendipity that led to several influential discoveries. He describes the purification and cloning of the CGRP receptor, the identification of receptor activity-modifying proteins (RAMPs), and the realization that CGRP signaling required receptor complexes rather than a single seven-transmembrane protein, reshaping thinking about peptide receptor activation and ligand binding. Dr. Foord also discusses work on angiotensin, GABA B, free fatty acid, nicotinic acid, and prostaglandin EP4 receptors, showing how orphan receptors were deorphanized using expression systems, electrophysiology in Xenopus oocytes, and early bioinformatics. The discussion highlights the gap between identifying a target and delivering a drug, the challenges of target validation, and the realities of industrial decision-making around receptor selectivity, safety, and market focus. Along the way, Dr. Foord reflects on the limits and promise of human genetics, the underexploited potential of GPCR antibodies, and the importance of team composition, negative data, and scientific community in navigating complex receptor biology. About the Guest Dr. Foord is a physiologist and pharmacologist who spent more than two decades at Glaxo, Glaxo Wellcome, and GlaxoSmithKline working on GPCR pharmacology and drug discovery. Trained in neuroendocrinology, he helped bring molecular biology into traditionally pharmacology-driven GPCR programs and worked across migraine, cardiovascular, pain, and inflammation projects. His work contributed to the identification of RAMPs in the CGRP receptor system, deorphanization of several GPCRs including GABA B and carboxylic acid receptors, and discovery of a prostaglandin EP4 modulator that advanced as a drug candidate. Later in his career, Dr. Foord led bioinformatics for neuroscience and played a central role in GSK’s early large-scale genetics initiative, integrating GPCR targets, ion channels, transporters, and ligands into association studies. His experience spans receptor cloning, expression systems such as Xenopus oocytes, electrophysiology, molecular pharmacology, and the use of informatics to mine sequence, structural, and genetic data for new receptor targets. Key Insights from the Conversation RAMPs Reframed Peptide GPCR Pharmacology . Dr. Foord explains how attempts to clone the CGRP receptor from SK-N-MC cells, combined with highly sensitive cAMP readouts in Xenopus oocytes, unexpectedly pulled out RAMP1 rather than a conventional seven-transmembrane receptor. The realization that RAMPs co-assemble with CRLR to form CGRP and related receptors forced a reconceptualization of peptide receptor activation and made clear that receptor complexes, not single proteins, could underlie pharmacological specificity. Serendipity Depends on Experimental Design and System Choice . The discovery of RAMPs was only possible because the assay tied receptor signaling to a highly amplified electrophysiological readout, revealing dramatic effects that might have been lost in noisier systems. Similarly, placental tissue became the source for CGRP receptor purification simply because binding studies showed it combined high receptor density with practical availability, illustrating how pragmatic choices in model systems can open unexpected paths in GPCR pharmacology. Deorphanizing Receptors Blends Bioinformatics and Bench Work . Dr. Foord describes a period where his group repeatedly identified ligands for orphan receptors: the second GABA B subunit via yeast two-hybrid, a carboxylic acid receptor when the solvent turned out to be the real agonist, and a nicotinic acid receptor by intersecting tissue expression data with orphan GPCRs. These stories show how careful pharmacology, informed sequence analysis, and attention to apparent artifacts can reveal new receptor signaling pathways relevant for metabolism and cardiovascular disease. Target Validation Is Harder Than Cloning a Receptor . From the non-existent second AT1 angiotensin receptor to the MAS oncogene as a poor angiotensin responder, Dr. Foord emphasizes how easy it is to be misled by overexpressed systems and noisy orphan receptor data. Southern blotting, cross-hybridization, and later genetic analyses ultimately showed that some hypothesized subtypes were artifacts, underscoring that robust target validation is a distinct and often more challenging problem than receptor cloning or initial ligand binding assays. Drug Discovery Is Constrained by Selectivity, Safety, and Strategy . The CGRP story illustrates how structural biology and pharmacology intersect with corporate decisions: once it became clear that the CRLR binding pocket is shared across CGRP, amylin, and adrenomedullin receptors, small-molecule selectivity looked problematic. Later hepatotoxicity concerns and the success of antibody therapeutics further shifted strategy. Similar strategic considerations shaped the fate of the EP4 partial agonist that ultimately found a niche in veterinary medicine rather than human rheumatoid arthritis. Genetics and Informatics Offer Power but Not Simple Answers . As Head of Bioinformatics for Neuroscience, Dr. Foord participated in GSK’s early large-scale association genetics effort, feeding GPCRs, ion channels, and transporters into case–control studies. Apart from APOE4 in Alzheimer’s disease, most signals failed to reach robustness with available cohort sizes, tempering expectations that genetics alone would deliver pipelines of GPCR targets. He argues that integrating structural biology, computational pharmacology, and genetics may still be key to understanding receptor activation in patients, but requires realistic views of effect sizes and trial design. Scientific Careers Depend on Teams, Mentors, and Community . Reflecting on his path from physiology to molecular pharmacology to bioinformatics, Dr. Foord highlights how good mentors, diverse teams, and open sharing of reagents and ideas enabled progress. He stresses the value of lab “optimists and cynics,” the importance of talking about negative results, and the role of informal networks in preventing wasted effort. For younger scientists, his advice centers on doing work you genuinely enjoy, finding supervisors who connect you to the broader GPCR community, and being willing to pivot as new methods and questions emerge. Episode Timeline 00:00 — Early academic work in neuroendocrinology, self-experimentation with TRH and somatostatin, and first encounters with hormones and GPCRs. 02:00 — Move to Roger Craig’s lab, purification of the CGRP receptor from human placenta, and practical considerations in choosing receptor-rich tissues. 05:00 — Transition from academia to Glaxo, early HIV TAT work in Xenopus oocytes, and the emergence of molecular pharmacology within a pharmacology-led organization. 10:30 — Expression cloning of the CGRP system, discovery of RAMP1, and how oocyte electrophysiology revealed a massive potentiation of endogenous CRLR signaling. 18:00 — Industrial migraine programs, small-molecule CGRP antagonists, challenges with selectivity and liver toxicity, and the later success of CGRP antibodies. 20:00 — Angiotensin receptor work, using Southern blots to hunt for a non-existent AT1 subtype, and the MAS oncogene as a cautionary tale in receptor signaling artifacts. 30:00 — Discovery of the prostaglandin EP4 receptor while searching for angiotensin-related sequences, development of an EP4 partial agonist, and its path into veterinary medicine. 34:00 — GABA B receptor complex, identification of the second subunit via yeast two-hybrid, and closing the chapter on proposed additional GABA B subtypes. 39:00 — Large-scale genetics and bioinformatics at GSK, expectations for GPCR target discovery from association studies, and reflections on why many signals remained elusive. 52:00 — Career advice on doing work you enjoy, the importance of mentors and connectedness, and how team composition and negative data shape GPCR research and drug discovery. Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Empowering Drug Discovery for the GPCR Community with Dr. Justin English About Dr. Justin English "Dr. English earned his PhD at UNC Chapel Hill in the laboratory of Dr. Henrik Dohlman and performed his postdoctoral work with Dr. Bryan Roth at the same University. We moved to Salt Lake City, Utah in 2020 to begin his own laboratory in the Department of Biochemistry at the University of Utah School of Medicine. His lab focuses on developing and innovating technologies to solve broad questions in pharmacology, with a specific focus on G-protein coupled receptor signaling and biology." Dr. Justin English on the web The English Lab University of Utah Google Scholar LinkedIn Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Inês Pinheiro, Monserrat Avila Zozaya & Yamina Berchiche About Inês Pinheiro PharmD by training and Ph.D. candidate in Hartley's lab at the University of Geneva. As a young researcher fascinated by chemokine receptors, molecular pharmacology, drug discovery, and immuno-oncology. Inês Pinheiro on the web LinkedIn University of Geneva Twitter Dr. GPCR Ecosystem About Monserrat Avila Zozaya I am a cell biologist interested in studying GPCRs, especially adhesion GPCRs. Motivated by my scientific passion, I recently started a postdoctoral fellowship to study the role of GPCRs in the mechanisms of pain and its comorbidities. Monserrat Avila Zozaya on the web Antony Boucard Lab Dr. GPCR Ecosystem About Yamina Berchiche Dr. Yamina A. Berchiche is the founder of Dr. GPCR, an ecosystem designed to bring together stakeholders interested in using G-Protein Coupled Receptors (GPCRs), that control virtually everything in the body, as drug targets. The mission of Dr. GPCR is to accelerate GPCR drug discovery by sharing the latest research and technology advances in the field and providing exposure to scientists through the Dr. GPCR podcast. Dr. Berchiche obtained her Master’s and Ph.D. in Biochemistry at the University of Montreal in Canada before training at The Rockefeller University in New York and the National Institutes of Health in Bethesda, Maryland. She developed expertise over the past two decades studying structure/function relationships of GPCRs using live-cell bioluminescence resonance energy transfer (BRET). Her work focused on chemokine receptors, members of the GPCR family that control cell movement in the body. Yamina Berchiche on the web Website LinkedIn Facebook Twitter ResearchGate PubMed Google Scholar Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Yamina Berchiche About Dr. Yamina Berchiche Dr. Yamina A. Berchiche is the founder of Dr. GPCR, an ecosystem designed to bring together stakeholders interested in using G-Protein Coupled Receptors (GPCRs) that control virtually everything in the body as drug targets. The mission of Dr. GPCR is to accelerate GPCR drug discovery by sharing the latest research and technology advances in the field and providing exposure to scientists through the Dr. GPCR podcast. Dr. Berchiche obtained her Master’s and Ph.D. in Biochemistry at the University of Montreal in Canada before training at Rockefeller University in New York and the National Institutes of Health in Bethesda, Maryland. She developed expertise over the past two decades studying structure/function relationships of GPCRs using live-cell bioluminescence resonance energy transfer (BRET). Her work focused on chemokine receptors, members of the GPCR family that control cell movement in the body. Dr. Yamina Berchiche on the web Website LinkedIn Facebook Twitter ResearchGate PubMed Google Scholar Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

From chemokine receptors at Rockefeller to founding Dr. GPCR during COVID — the career arc behind the ecosystem built for the field's unreached receptors. << Back to podcast list Strategic Partner(s) Yamina Berchiche: Beyond the Lab — From Chemokine Receptors to the Dr. GPCR Ecosystem Dr. Yamina Berchiche spent two decades working on G protein-coupled receptors at the bench — training that spanned chemokine receptor conformational dynamics at the Université de Montréal, CXCR3 splice-variant signaling at Rockefeller University in Dr. Tom Sakmar's lab, CRISPR knockout generation at NIAID, and class B peptide receptor work at Generate Biomedicines. Across those stops, one observation kept resurfacing: the GPCR field is enormous — roughly 400 non-olfactory receptors — but clinical drug discovery has reached only about 166 of them, leaving more than 250 receptors unstudied at anything close to therapeutic depth. This conversation traces the scientific arc that led Dr. Berchiche to leave the bench after a COVID-era redundancy, and examines the motivation behind founding Dr. GPCR — an ecosystem of podcasts, newsletters, summits, and working spaces designed to give the field connective tissue it has historically lacked. For Dr. Berchiche, this work is personal: the receptors she helped characterize for years belong to a family she believes has been collectively underserved by the infrastructure around it, and building that infrastructure has become a full-time scientific question in its own right. About the Guest Dr. Yamina Berchiche is the founder of the Dr. GPCR ecosystem and the host of the Dr. GPCR Podcast. She holds a PhD in Biochemistry from the Université de Montréal, where she trained in Dr. Nikolaus Heveker's lab at the CHU Sainte-Justine Research Center on chemokine receptor structure–function relationships, with extensive collaborative work in Dr. Michel Bouvier's lab on BRET-based conformational readouts. She completed postdoctoral training at Rockefeller University in Dr. Tom Sakmar's lab, where she characterized the signaling diversity of three alternative splice variants of CXCR3. Her career has moved through academic pharmacology, a research fellowship in B-cell molecular immunology at NIAID, and a senior scientist role at Generate Biomedicines, where she worked on class B peptide receptor engineering using AI-driven protein design. She now builds scientific community infrastructure for the GPCR field. Scientific Themes of the Conversation Chemokine receptor redundancy and the shift toward functional selectivity as a framework Splice variants as signaling variants — CXCR3 as a case study for transcript-level diversity The orphan-majority problem in GPCR drug discovery — why ~250 non-olfactory receptors remain outside clinical attention Career architecture for bench pharmacologists moving beyond academia and biotech Scientific community as infrastructure — what connective tissue a 400-receptor field actually needs Assay design as the lever that shifts conceptual frameworks Key Insights from the Conversation Rejection as redirection. The summer placement Dr. Berchiche didn't get in Michel Bouvier's lab led her to Nikolaus Heveker's newly opened lab at CHU Sainte-Justine, where she was the first student. The lab had no equipment, only stacks of bills on every bench — and a research program on chemokines and chemokine receptors that would define her career. The redundancy assumption crumbled under better assays. The chemokine system — roughly 50 ligands for 20 receptors — was framed for decades as redundant because multiple chemokines bind multiple receptors. Dr. Berchiche's thesis work on CXCR4 mutants and her PhD characterization of natural chemokines binding CCR2B showed the opposite: distinct ligands activate distinct signaling outputs, and functional selectivity was quietly hiding inside what had been called promiscuity. Splice variants aren't just structural — they signal differently. Her Rockefeller work on the three alternative splice variants of CXCR3, initially prompted by a simple question from Tom Sakmar, demonstrated that variants encoded by the same gene can recruit different signaling outputs in response to the same ligands. The implication: transcript-level diversity is itself a signaling mechanism, not a cloning artifact to be collapsed away. The 250-receptor problem sits in plain sight. Of roughly 400 non-olfactory GPCRs, only about 166 are being targeted or studied for clinical application. The remaining 250+ are not obscure — they are simply not connected to drug-discovery momentum. This gap, visible in the 2017 mapping work by Dr. Alexander Hauser and colleagues, is the motivating tension behind Dr. GPCR. The 30,000-foot view requires leaving the bench. After nearly two decades in the lab, Dr. Berchiche found that deep focus on one project was no longer fulfilling. The bench scientist's perspective — which she explicitly values — comes at the cost of the field-level view that ecosystem-building requires, and choosing between them turned out to be a real career architecture decision rather than a detour. Community is scientific infrastructure, not marketing. A podcast, a monthly newsletter, and a virtual summit are not promotional surfaces. They are the connective tissue a 400-receptor field uses to exchange techniques, ideas, and trust across institutional boundaries. Without that tissue, GPCRs stay siloed by receptor family and by lab. Building during a pandemic is a design constraint, not a footnote. Dr. GPCR was founded in March 2020 after a COVID-era redundancy at Generate Biomedicines. Early episodes were recorded in a Toyota Prius parked outside a gym with public Wi-Fi, and then in a closet studio her husband built so she could keep the AC running without bleeding background noise into the audio. The ecosystem's physical origins are inseparable from its founding conviction. Episode Timeline Timestamps were generated using AI for readability. 00:00 Introduction 02:25 The closet studio and what's in the talk 04:00 From Oradea to Montreal — the geography of a GPCR career 06:30 An empty lab and the chemokine redundancy problem 09:00 A master's, old-school molecular biology, and an accelerated JBC paper 11:00 CCR2B, functional selectivity, and a stellar reviewer moment 14:00 Rockefeller, CXCR3, and three splice variants that weren't the same 17:00 NIH and the pull toward a 30,000-foot view of the field 21:00 COVID, redundancy, and the 250 GPCRs nobody studies 23:08 Building the Dr. GPCR ecosystem 32:28 Q&A — preparing an episode, funding, and what's next 46:53 Recording Brian Roth from a Prius — the closet-studio origin story Selected Quotes "You have 400 non-olfactory GPCRs. Only about 166 of them are being targeted and studied for clinical applications. But you have 250-plus receptors that are not well characterized enough and are not considered for the treatment of any diseases." "If you want to advance the field and you want to drug GPCRs better, the point is not to show that you can pipette, but the point is to get to that result." "At NIH, I decided that I wanted to go what you'd call the dark side, which I don't think it's the dark side." "Brian throughout his career was told so many times that he should quit science. And thank God he did not quit science. That's the kind of story that I like to share in the podcast." About this episode GPCRs have played a central role in my scientific career ever since I took Dr. Michel Bouvier’s class as an undergraduate student at the University of Montreal in early 2000. During the past 2 decades, my research mainly focused on chemokine receptor structure/function relationships. For the purposes of this presentation, I will walk you through my various career experiences and include the skills I learned during each experience, which ultimately led me to found Dr. GPCR. Last, I will give an overview of the various programs we established at Dr. GPCR, present our team as well as provide you with a sneak peek of our future podcast guests and more. I gave a talk on October 12th at the 3rd ERNEST meeting about the Dr.GPCR Ecosystem . I want to say thank you to the ERNEST meeting organizers for the invitation with special thanks to Dr. Martha Summer and Dr. Alexander Hauser , and Luise Wagner . For more information about the ERNEST network, visit https://ernest-gpcr.eu/ . Dr. Yamina Berchiche on the web D r. GPCR Ecosystem Member Website LinkedIn Publications Twitter Facebook Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Nyla Naim, Dr. Michael Lemieux & Dr. Jason Nasse About Dr. Nyla Naim Nyla is a Senior Scientist on the Scientific Support Team at Addgene . She received her Ph.D. at the University of Pittsburgh and continued her postdoctoral research at the University of Vermont studying cellular signaling, biosensors, and optogenetics. Nyla supports biomedical research by connecting researchers with resources and promoting reproducible science. Dr. Nyla Naim on the web LinkedIn Dr. GPCR Ecosystem About Dr. Michael Lemieux ''My name is Michael (Mike) Lemieux and I am a Connecticut native. I completed my Ph.D. in molecular and cell biology at UConn and then joined Addgene as a Quality Control Scientist in 2015. Since then I transitioned into a Scientific Support role to leverage my passion for helping people! Beyond my interest in science, I am a strong advocate for graduate education reform and I love to write.'' Dr. Michael Lemieux on the web Addgene Blog Dr. GPCR Ecosystem About Dr. Jason Nasse Dr. Jason Nasse is a senior scientist at Addgene specializing in the use of AAV viral vectors. He obtained his Ph.D. in Neuroscience from Ohio State University focusing on synaptic plasticity and adrenergic receptor modulation of both pre-and postsynaptic properties. By taking a very non-traditional path to obtain a Ph.D. Dr. Nasse has had the opportunity to experience how science is performed across different sectors and around the country. Prior to his role at Addgene, Jason held roles in academia, big pharma, and non-profit research organizations. Dr. Jason Nasse on the web LinkedIn Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. Paul Insel explains how unbiased GPCR expression profiling uncovered overlooked receptors in cancer — and why the field may need to rethink which GPCRs matter most. << Back to podcast list Strategic Partner(s) Paul Insel: Unbiased Discovery and the GPCRs We've Been Missing The GPCR field has produced thousands of studies on a small number of well-characterized receptors. But what if the ones that matter most in human disease are the ones we haven't prioritized? Dr. Paul Insel's lab at UC San Diego has pursued this question using unbiased expression profiling — GPCR arrays, RNA-seq, and single-cell analysis — to catalog which receptors are actually highly expressed across human tissues and disease states. In pancreatic cancer, proton-sensing GPCRs such as GPR68 are dramatically upregulated in cancer-associated fibroblasts, creating feedback loops between the tumor microenvironment and stroma that may drive disease progression. Across 45 cancer types, numerous GPCRs show elevated expression without corresponding mutations — a pattern the mutation-centric oncology paradigm has largely missed. For Dr. Insel, this shift began with a single dataset — a postdoc's unbiased expression profile showing the most abundant receptor in a normal human cell type had almost no literature behind it. Listeners will gain perspective on how asking broader questions about receptor biology can reshape drug discovery priorities. About the Guest Dr. Paul Insel is Distinguished Professor of Pharmacology and Medicine at the University of California, San Diego. His research spans four decades of GPCR signaling, from cyclic AMP and adrenergic receptor biology to purinergic receptors and, most recently, proton-sensing GPCRs in the tumor microenvironment. His lab combines bioinformatic analysis of GPCR expression across human cancers with wet-lab validation in animal models, particularly in pancreatic cancer. Dr. Insel also directs UCSD's MD-PhD Medical Scientist Training Program, a role he has held for over 30 years. Scientific Themes of the Conversation Unbiased receptor discovery — Why hypothesis-free expression profiling reveals GPCRs that decades of targeted research missed GPCRs in the tumor microenvironment — Proton-sensing receptors, cancer-associated fibroblasts, and the role of low pH in tumor signaling Drug repurposing through receptor mapping — Identifying already-approved drugs that target overexpressed GPCRs in cancer Reductionism vs. native cell biology — The limits of studying purified components and the case for understanding receptors in intact cellular environments Biased signaling in practice — Why the promise of biased agonism is more complicated than the field hoped Breadth as a scientific strategy — How reading across disciplines and resisting premature narrowing drives discovery Key Insights from the Conversation 1. The biggest discoveries came from asking what was being overlooked Dr. Insel's late-career pivot began with a deceptively simple question: are we studying the right GPCRs? When his lab ran unbiased expression profiles on normal human cells, the most highly expressed receptor — PAR1 — had almost no functional literature behind it. Nature had placed it at the top; science had barely looked. 2. Proton-sensing GPCRs create a feedback loop in pancreatic cancer GPR68 is dramatically upregulated in cancer-associated fibroblasts — not the cancer cells themselves. The tumor signals fibroblasts to raise GPR68 expression, and the low pH of the tumor microenvironment then activates that receptor, which signals back to promote cancer survival. It is a positive feedback loop that exploits the acidic environment tumors naturally create. 3. GPCRs are overexpressed across dozens of cancers — without mutations A large bioinformatic study from Dr. Insel's lab examined GPCR expression across 45 human cancer types and found widespread over expression without corresponding increases in copy number or mutation frequency. This challenges the mutation-centric framework that dominates oncology and suggests GPCRs may contribute to pathophysiology through expression changes alone. 4. The field's reductionism may be hiding how receptors actually work Dr. Insel has long argued that purifying receptors, depleting GTP, and stabilizing conformations through mutations teaches us about components — not about how cells actually use them. He compares the biochemist's approach to smashing a television with a wrecking ball and trying to reassemble the pieces to understand how it works. 5. Biased signaling is real but harder to exploit than expected GPR68 couples to both Gq and Gs, and the functional effects in cancer-associated fibroblasts appear to run primarily through Gs. In principle, biased antagonists could selectively block the disease-relevant pathway. But Dr. Insel is cautious — signaling bias operates on a conformational continuum, and clinical translation has not yet matched the elegance of the concept. 6. A career redirected by a dinner and an empty schedule In 1975, Dr. Insel was the only unmarried scientist at a dinner with Al Gilman. The group needed someone to visit Gilman's lab to learn radioligand binding — and he was the one with nothing else to do. That accidental assignment launched a career in GPCR signaling that has now spanned over four decades. 7. The "unknown unknowns" should change how we fund and train scientists Dr. Insel believes the training system pushes young researchers to narrow too early, at the cost of the cross-disciplinary thinking that leads to real discoveries. His own career has been shaped by reading broadly and importing ideas from other fields — a strategy he sees as increasingly essential as GPCR biology intersects with cancer, immunology, and systems biology. Episode Timeline 00:00 Introduction and context 01:08 Dr. Insel's path from medicine to molecular pharmacology 05:15 The origin story — dinner with Al Gilman and the start of a GPCR career 09:06 Evolving receptor loves: from adrenergic to purinergic to proton-sensing GPCRs 13:19 Proton-sensing GPCRs: what they are and why they matter 16:18 GPR68 and the feedback loop in pancreatic cancer 19:46 Challenges of targeting GPCRs in oncology — funding, skepticism, and the mutation paradigm 25:05 AI, in silico screening, and the limits of computational drug discovery without structures 31:33 Biased signaling: promise, complexity, and caution 35:00 The case against reductionism — why native cell biology matters 38:05 Advice for young scientists: think broadly, resist narrowing too fast 42:14 Aha moments — the data that changed the direction of a lab 47:30 The future of the GPCR superfamily and the work still to be done Selected Quotes "I said, which receptors are the highest expressed? And the answer was PAR1, the thrombin receptor. So I did what anyone would do — I looked up what's known about it. And the answer was nothing." "We don't know what we don't know. And I think that's been a real driver for how I've approached the last several years of my scientific effort." "If you ask a biochemist how does a television work, he would probably take a wrecking ball to it and then try to piece all the little parts back together." "Nature decided, for reasons that none of us will ever probably know for sure, that GPCRs should be the largest receptor membrane family. And there's still a lot to be learned." About this episode In 1975, Dr. Paul Insel was at the FASEB experimental biology meeting in Atlantic City. During dinner with colleagues and Alfred Gillman , co-recipient of the 1994 Nobel Prize in Physiology or Medicine for their discovery of G-proteins and their role in signal transduction in cells, Paul was designated to go to Gillman’s lab . That summer, he used radioligand binding methods to dissect receptor function from the adenylyl cyclase activated by ligands, including adrenaline. From that point on, Paul was hooked and has since studied receptor function in human physiology, receptor molecular pharmacology in cells, and animal models, and as he puts it has now he’s "gone full circle" back to studying GPCRs important in human pathophysiology. Today, Paul and his team focus on previously unrecognized receptors with the hopes to use these as novel drug targets. Dr. Paul Insel on the web Insel Laboratory Institute of Engineering in Medicine UC San Diego UCSD Profiles Google PubMed Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

When his lab closed in 2020, Dr. Paul Insel turned dry-lab science into a reframing of COVID-19 pathobiology as a GPCR signaling imbalance — and a figure in The Economist. << Back to podcast list Strategic Partner(s) Paul Insel: Rethinking COVID-19 Pathobiology Through GPCR Signaling In the spring and summer of 2020, pharmacologist Dr. Paul Insel did something unusual for a working lab scientist: he stopped pipetting, and started writing. With his UC San Diego postdoc Krishna Sriram, he reread the literature on ACE inhibitors and angiotensin receptor blockers in the context of severe acute respiratory illness and concluded — against a swell of clinical panic — that the case for their danger in COVID-19 didn't hold up. What came next was a series of papers reframing severe COVID-19 as a disease of signaling imbalance: an overdrive of AT1R activation by angiotensin II, paired with a loss of ACE2-generated angiotensin 1-7. The therapeutic logic that follows is less about attacking the virus and more about rebalancing a GPCR-driven system that the infection has thrown off-axis. A figure from that British Journal of Pharmacology paper was later redrawn by The Economist for a general-audience article on COVID pathobiology — an unexpected crossover for work that began as armchair science during a lockdown walk. This conversation matters to Dr. Insel personally because he is, in his own words, a vulnerable patient — immunosuppressed, older, asthmatic — and what he's describing is not abstract. It's what he would want a physician to understand if he were the one in the hospital bed. About the Guest Dr. Paul Insel is Distinguished Professor of Pharmacology and Medicine at UC San Diego, where he also co-directs the MD-PhD program. His research career has centered on GPCR signaling — with particularly deep work on beta-adrenergic receptors, cyclic AMP regulation, and receptor biology across tissue systems. Beyond the lab, he has been a long-standing contributor to the Goodman & Gilman textbook of pharmacology and is writing its next chapter on angiotensin signaling and angiotensin drugs. He is also involved nationally in MD-PhD program leadership. Scientific Themes of the Conversation The angiotensin imbalance hypothesis of COVID-19 pathobiology — AT1R overdrive versus ACE2/Ang 1-7 insufficiency Drug repurposing as a pandemic strategy — from ACE inhibitors and ARBs to PAR1 and PAR4 antagonists The "gas pedals and brakes" philosophy of cell signaling and pharmacology Dry-lab pharmacology and what becomes possible when wet-lab work stops GPCR density and tissue-specific therapeutic opportunity — type II pneumocytes, beta-2 receptors, and the asthma parallel The ethics of acting on conviction — off-label drug use during a pandemic Key Insights from the Conversation The ACE inhibitor scare was built on a bogus reading of the literature. Early in the pandemic, senior clinicians were stopping their own ACE inhibitors and ARBs based on hypothesis-driven fears of worse outcomes. Dr. Insel and Krishna Sriram went to the primary data and concluded the claim was not supported. The review was accepted at Clinical Pharmacology and Therapeutics within weeks. Severe COVID-19 may be a story of signaling imbalance, not just viral damage. The British Journal of Pharmacology paper reframes pathobiology as an imbalance between AT1R activation and ACE2-generated angiotensin 1-7. If the virus disrupts one arm of this receptor-peptide system, the therapeutic question stops being "what do we add?" and becomes "what do we rebalance?" Biology runs on opposing forces, and good pharmacology learns to see them. Kinases and phosphatases. Cyclases and phosphodiesterases. ACE1 and ACE2. Dr. Insel returns repeatedly to his "gas pedals and brakes" frame — a lens that has quietly shaped how he reads both disease mechanism and drug targets across a long career. The lung's beta-2 story has been sitting in plain sight for fifty years. Type II pneumocytes carry the highest beta-2 receptor density in the body. Long-acting beta-agonists paired with glucocorticoids have been the mainstay of asthma treatment for decades. The connection to acute respiratory distress syndrome — and to the mechanism through which dexamethasone actually works — is, in his reading, underdiscussed rather than speculative. "Don't just do something. Stand there." A clinical mentor's line that became the frame for the lockdown months. Four papers in roughly two months — what Dr. Insel calls armchair science. Not casual, not opinion-writing; dry-lab pharmacology done with the same seriousness as bench work, just with different tools. A figure can travel further than the paper it came from. The schematic from the BJP paper was redrawn by The Economist, with attribution, for a general-audience article on COVID pathobiology. Dr. Insel notes wryly that it's the only paper his family has ever really responded to. The ethics of acting on conviction is its own paper. Midway through writing the angiotensin work, Dr. Insel realized no one had written criteria for how to decide about off-label use of a drug during a pandemic — when mechanism is compelling, safety is reasonable, and trial evidence isn't there yet. He is writing that paper with an ethicist and a law-school colleague. It is exactly the kind of work a pharmacologist does when the lab is closed. Episode Timeline Timestamps were generated using AI for readability. 00:00 Opening and 2020 Summit context 01:45 Dry-lab science — how the work shifted when the wet lab closed 02:37 Rereading the ACE inhibitor scare — and the BJP paper that followed 07:40 Expanding the hypothesis — PAR1, PAR4, and upstream pathobiology 11:00 Gas pedals and brakes — biology's architecture of opposing forces 14:00 Type II pneumocytes, beta-2 density, and the asthma parallel 22:40 The ethics of off-label drug use during a pandemic 25:00 Genetic determinants of severity — ACE1 isoforms and population data 28:40 Vaccine development speed and public trust 33:40 Staying sane — pickleball, walking, and community Selected Quotes "Don't just do something. Stand there. That's sort of what we've been doing. And I think we've made some contributions that are pretty interesting. I really want to do something to help people. That's what this is all about, really." — Dr. Paul Insel "Almost most biological systems are all about gas pedals and brakes. We have kinases and phosphatases. We have cyclases that make cyclic AMP and phosphodiesterases that degrade it. Nature has built in these systems consistently." — Dr. Paul Insel "If you would have told me three months ago that I was going to end up having a figure in The Economist — forget about one of the science journals — in The Economist…" — Dr. Paul Insel "It's still about GPCRs." — Dr. Paul Insel About this episode Dr. Paul Insel is currently a Distinguished Professor of Pharmacology and the University of California San Diego. Paul thinks broadly about science and has been actively publishing papers about his ideas on how COVID symptoms could be treated while we wait for a vaccine, particularly about ACE2 and angiotensin. For the past 30 years, he has been the Director of MD/Ph.D. training program at UCSD and has served as Editor or Senior Editor of numerous scientific journals, including but not limited to the Journal of Clinical Investigation, Molecular Pharmacology, British Journal of Pharmacology, and American Journal of Physiology-Cell Physiology. Dr. Paul Insel on the web Insel Laboratory Institute of Engineering in Medicine UC San Diego UCSD Profiles Google PubMed Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Gunnar Schulte of Karolinska Institute makes the case that frizzled receptors are GPCRs — through G-protein coupling maps, conformational biosensors, and the first small molecule shown to activate frizzled 6. << Back to podcast list Strategic Partner(s) Gunnar Schulte: Frizzled Receptors and the GPCR Identity Question Frizzled receptors are a family of 10 cell surface proteins that mediate Wnt signaling — one of the most fundamental pathways in vertebrate development, stem cell renewal, and tumor biology. Despite decades of study, the field remains divided on a foundational question: are frizzled receptors GPCRs? They carry the characteristic seven-transmembrane topology, but their ligands are large, lipid-modified proteins that require carrier molecules for transport, their canonical Wnt–beta-catenin signaling appears G-protein-independent, and almost no small molecule pharmacology exists for this subfamily. Gunnar Schulte's lab at Karolinska Institute has spent years assembling the evidence on the other side — demonstrating G-protein coupling specificity across individual frizzled subtypes, detecting ligand-induced conformational changes through biosensor approaches that mirror what is seen in classical GPCRs, and showing that G-protein-dependent pathways downstream of frizzled activation are physiologically relevant. For Schulte, the scarcity of pharmacological tools is not just a technical inconvenience — it is the central obstacle that has shaped every decision his lab has made since his first postdoc. The question of whether frizzled receptors are GPCRs is, in his view, inseparable from the question of whether they can ever be drugged. About the Guest Gunnar Schulte is a professor at the Department of Physiology and Pharmacology at Karolinska Institute in Stockholm, where he leads research on Wnt–frizzled receptor signaling. His lab investigates the molecular mechanisms of frizzled receptor activation, including G-protein coupling specificity across all 10 human frizzled subtypes, receptor conformational dynamics, and biosensor platforms for quantifying signaling selectivity. Schulte's work helped establish that individual frizzled receptors are not interchangeable — each couples to distinct G-protein families in ways that challenge the field's conventional focus on the beta-catenin pathway alone. He began his scientific career studying adenosine receptor signaling during a PhD with Bertil Fredholm at Karolinska, and pivoted to frizzled receptors during a postdoctoral fellowship with Ernest Arenas, staying at the same institution ever since. Scientific Themes of the Conversation The GPCR identity question — what it takes to make the case, and why the field is still divided G-protein coupling specificity across the 10 frizzled subtypes — each receptor is its own pharmacological entity The Wnt ligand problem — lipid modifications, carrier proteins, and what makes these ligands so difficult to work with Conformational dynamics as functional evidence — how biosensors are being used to argue for GPCR-like activation in frizzled Pathway selectivity — how the receptor may choose between disheveled and G-protein signaling through conformational selection The pharmacology gap — small molecules, repurposed Smoothened compounds, and what a druggable frizzled might eventually look like Key Insights from the Conversation 1. Each frizzled receptor is its own pharmacological entity The frizzled family is commonly discussed as a single target class, but Schulte's G-protein coupling data reveal that individual subtypes are functionally distinct. Frizzled 5 couples to Gq, frizzled 7 to Gs, frizzled 10 to G13 — and the pattern continues across the family without a simple organizing rule. Treating "frizzled" as a unified target, Schulte argues, is one reason the field has been slow to build pharmacology. 2. The Wnt ligand problem may be the field's deepest bottleneck Wnt ligands are approximately 35–40 kDa, carry a lipid modification that prevents them from diffusing freely in aqueous medium, and require carrier proteins to reach their receptors. Fewer than one in 19 Wnt ligands is currently available in a biologically active, tagged form suitable for binding assays. Schulte describes spending a substantial portion of his lab budget on recombinant Wnts while still unable to run the systematic interaction mapping the field needs. 3. Conformational change is Schulte's strongest argument for GPCR identity Using cpGFP-based conformational sensors inserted into frizzled receptors, Schulte's lab has shown that Wnt stimulation produces detectable conformational changes that parallel what is observed in classical GPCRs. For Schulte, this is not secondary evidence — it is the clearest demonstration that frizzled receptors operate by the same fundamental activation mechanism, and the clearest challenge to those who believe otherwise. 4. A Smoothened compound became the first pharmacological handle on frizzled SAG1.3, a small molecule agonist originally developed for the related receptor Smoothened, was shown by Schulte's lab to act as a weak partial agonist at frizzled 6. Every chemical modification so far has converted it into an antagonist rather than a stronger agonist. But the result was the first demonstration that frizzled receptors have a pharmacologically accessible binding pocket — a conclusion that was not obvious from the initial frizzled 4 crystal structure, which suggested the pocket was too small for small molecule targeting. 5. The class F CRISPR knockout cell line changed what questions could be asked Working in cells that endogenously express multiple frizzled subtypes makes it nearly impossible to attribute a signaling event to a single receptor. The development of a HEK cell line with all class F receptors knocked out — generated by Benoît Vanhollebeke's lab in Belgium and shared with the field — gave Schulte's group the clean background needed to study individual frizzled subtypes in isolation. Combined with porcupine inhibitors to suppress endogenous Wnt secretion, this system has become what Schulte describes as one of the most important practical advances the field has seen in years. 6. Disheveled may regulate access to both G-protein and beta-catenin pathways through conformational selection Disheveled (DVL), the scaffolding protein downstream of frizzled, is not simply a beta-catenin pathway component. Schulte's lab has preliminary evidence that disheveled undergoes conformational selection at the receptor — analogous to the way G proteins adopt receptor-stabilized conformations before activating. This would mean the receptor itself determines whether a signal flows through disheveled or through a G protein depending on its conformational state, a form of pathway selectivity that remains to be fully mapped in the frizzled system. 7. A PhD lesson in pharmacological humility that lasted 25 years During his thesis seminar, Schulte presented data attributing an unexpected signaling connection to a kinase pathway he had dissected with pharmacological inhibitors. His supervisor, Bertil Fredholm, asked a single question: had he checked whether those inhibitors were also antagonists at the adenosine receptors under study? Several were — the signal Schulte had mapped was an off-target receptor effect, not the kinase pathway he had concluded. He describes the experience as formative, and the lesson as one that has quietly shaped his approach to chemical probes ever since. Episode Timeline Timestamps are AI-generated from the transcript and may not reflect the final edited video exactly. 00:00 Introduction 00:48 From Berlin to Stockholm — a career redirected by armed robbery 08:30 The adenosine receptor talk that pulled Schulte into GPCRs 11:14 From adenosine to frizzled: the postdoc decision that defined the lab 17:43 Frizzled receptors: 10 subtypes, 19 ligands, almost no drugs 20:22 When Wnt–frizzled signaling goes wrong — cancer, fibrosis, nail dysplasia 28:23 G-protein coupling specificity across the frizzled family 34:55 SAG1.3: repurposing a Smoothened compound to activate frizzled 6 40:51 Where beta-arrestin and disheveled fit in Wnt signaling 47:01 The class F CRISPR knockout cell line that changed everything 53:43 Conformational change as the strongest argument for GPCR identity 01:03:11 Career advice: explore widely, then commit to a niche Selected Quotes "The frizzles look like GPCRs, but the field is somehow split in people who believe they are and other people who don't believe they are. The biggest question is how we don't understand how the ligand interacts with the receptor, how the receptor really gets activated and how signaling is initiated and specified." "I think that is one of the interesting advances — we understand that a frizzled in a signaling system is not necessarily only the abbreviation FZD. It's also a number, because the individuals of the family are different. And I think that is not really particularly appreciated in the field, because we didn't know so far." "We clearly see that Wnt stimulation changes the conformation of the frizzles that we have looked at in the same way, or a similar way, as the GPCR acts. That is my strongest argument for the GPCR nature of these receptors." "It's not like in the good old adenosine receptor times, that we have the small molecule available and get crystal clear tenfold increase of a kinase phosphorylation or something." About Dr. Gunnar Schulte Gunnar Schulte is a Professor in receptor pharmacology and research group leader for the section Receptor Biology and Signaling at the Department of Physiology and Pharmacology. He has a background in biochemistry from the Free University in Berlin/Germany and a Ph.D. in molecular pharmacology (supervisor: Bertil B Fredholm; 1998-2002) from Karolinska Institutet. As a postdoc, he trained first with Ernest Arenas (Karolinska Institutet, Molecular Neurobiology; 2003-2005) and later with Roger J Summers (Monash University, Melbourne Australia, GPCR pharmacology; 2006) before starting his independent research team "Receptor Biology & Signalling" in 2008. Gunnar Schulte is also the scientific secretary of the Swedish Society for Medical Research (SSMF) and a member of the editorial board/editorial advisory board of Molecular Pharmacology, British Journal of Pharmacology, Pharmacological Reviews, and The Journal of Biological Chemistry. General Research Interest: The focus in the Schulte lab is on Frizzled signaling and pharmacology aiming to understand the role of WNT/Frizzled signaling in biology, physiology, and disease. Most importantly my research team tries to understand underlying mechanisms of WNT-receptor interaction, the relevance of receptor dynamics, and receptor complex composition for signal initiation and specification. The ultimate aim is to use the new knowledge to find, create and optimize Frizzled-targeting small molecule drugs to improve future therapies of human disease. Dr. Gunnar Schulte on the web Schulte Lab LinkedIn Google Scholar Orcid YouTube Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Simone Prömel & Dr. Ines Liebscher About Dr. Simone Prömel Simone Prömel is currently a professor of cell biology at the Heinrich Heine University Düsseldorf, Germany. Being a biochemist by training, she completed her Ph.D. at the Institute of Biochemistry at the University of Oxford, UK. During this time, she discovered her love for Adhesion GPCRs and started delineating the molecular mechanisms of the Adhesion GPCR Latrophilin-1. These extraordinary receptors, about which there was not much known other than that they are huge and somehow play important roles in health and disease, fascinated her so much that she continued working on them when she started her own lab at Leipzig University. There she focused on the different modes of action of Adhesion GPCRs and found that they do not only mediate classical G protein signals into cells but can also communicate solely via their N termini. Today, she and her team are working on the questions of how Adhesion GPCRs integrate the different signals on a molecular level and how these are translated into physiological functions in various model organisms. Together with Ines Liebscher, Simone is leading an EU-funded COST Network on Adhesion GPCRs: CA18240 Adher´n Rise. Dr. Simone Prömel on the web Prömel Lab Pubmed Researchgate Twitter Dr. GPCR Ecosystem About Dr. Ines Liebscher Dr. Liebscher is a Professor at the Rudolf Schönheimer Institute of Biochemistry at the Medical Faculty of the Leipzig University. During her medical studies in Leipzig, she had her first encounter with an orphan GPCR as the subject of her MD thesis. Being faced with the vast unknown biochemical and pharmacological territory that would be helpful to study orphan receptors she enrolled in the MD/Ph.D. program of Leipzig University. Her postdoctoral work leads her to investigate a whole family of orphan receptors: adhesion GPCRs. With the little knowledge on these receptors available, there were multiple questions to tackle. Starting with proving and characterizing G-protein coupling, Ines spends several years studying the activation mechanism of adhesion GPCRs. In collaboration with great fellow adhesion GPCR scientists around the globe she established a tethered agonist -extracellular matrix- mechano-activation- activation scenario that forms the basis for her current projects that focus on the structural and physiological implications of these findings. Together with Simone Prömel, Ines is leading a COST Network on adhesion GPCRs: CA18240 Adher'nRise. Dr. Ines Liebscher on the web Website LinkedIn Researchgate Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Brian Arey on GPCR drug discovery from the inside - GPR56 mechanotransduction, the KLF2 pathway, organizational patience, and unpublished science. << Back to podcast list Strategic Partner(s) Brian Arey - Part 2: GPCR Drug Discovery and the Science Nobody Publishes Drug discovery in the pharmaceutical industry generates enormous volumes of foundational science that never reaches a journal. Target validation programs are built, defended, and sometimes cancelled before a single paper is submitted. The scientists who do this work accumulate expertise - in receptor signaling, cardiovascular physiology, mechanobiology - that exists in internal reports and institutional memory rather than the published record. In this conversation, Arey traces the full arc of how a pharmaceutical research program is born, resourced, and either advanced or discontinued. He describes his work on GPCR mechanotransduction in endothelial cells - including the early identification of GPR56 as a mechanical sensor and his sustained case for the KLF2 signaling pathway as a GPCR-linked therapeutic target in atherosclerosis - and is candid about what happens when organizational priorities shift and a program you believe in gets shelved. Arey's conviction that the KLF2-GPCR axis in vascular endothelium represents an underexplored route to treating atherosclerosis has not diminished with time. This episode is for scientists who want to understand what early drug discovery actually costs - and what it produces that the literature cannot capture. About the Guest Brian Arey is a pharmacologist and physiologist with over 25 years of pharmaceutical research experience at Bristol-Myers Squibb. His scientific work spans GPCR mechanotransduction in vascular endothelial cells, cardiovascular target validation, thrombosis pharmacology, and metabolic disease biology, with contributions to multiple clinical programs including preclinical models that supported the apixaban development program. He has led mechanistic pharmacology operations and served as interim head of a 70-person cross-functional research organization spanning mechanistic pharmacology, compound management, and core automation. His approach to drug discovery is grounded in classical physiology and driven by a willingness to enter fields - bone biology, thrombosis, endothelial function - with limited prior expertise and build toward the question the science is actually asking. Scientific Themes of the Conversation The architecture of drug discovery: from pathophysiology to program governance GPCR mechanotransduction in endothelial cells: GPR56, KLF2, and atherosclerosis Hypothesis discipline and the "killer experiment" in early discovery Intellectual humility and the dynamics of cross-functional drug discovery teams Career breadth across physiology systems: scientific advantage and professional cost Scientific identity, intuition, and the scientist who refuses the mold Key Insights from the Conversation Early discovery is the most creative and most invisible space in pharmaceutical research Arey describes early-stage drug discovery as structurally similar to academic research - hypothesis-driven, iterative, without guaranteed output. The difference is that the science is consumed by the organization rather than the literature. Scientists who build careers in this space often generate more foundational knowledge than their publication records reflect, and Arey is unusually candid about what that obscurity actually feels like from the inside. The "killer experiment" is the one designed to end your own program A mentor taught Arey the concept of the killer experiment: the definitive test engineered specifically to challenge your own hypothesis before more resources are committed. The discipline requires a willingness to invest in an outcome that might close what you have built. Arey calls this one of the most important and least instinctive skills in pharmaceutical research - and one that most scientists are never explicitly taught. GPR56 as a GPCR mechanosensor in endothelial cells - a decade ahead of the published literature Working on endothelial cell responses to shear stress, Arey identified GPR56 as a candidate mechanosensor before the concept had been established in print. A paper confirming the receptor's mechanotransduction function in endothelial cells appeared roughly ten years later. He describes the experience with something between resignation and dry satisfaction: he knew, the data supported it, and the field eventually arrived. The KLF2-GPCR axis in atherosclerosis: a program that ended, a conviction that did not Arey spent years building the case for GPCRs and the KLF2 transcription factor as a linked anti-inflammatory pathway in vascular disease. The program was eventually deprioritized as oncology absorbed industry attention. His belief in the biology has not changed. He says so directly: "somebody please do it" - not as a rhetorical gesture, but as a genuine ask to whoever is listening. Breadth across physiology systems carries a professional cost that nobody warns you about Moving between neuroscience, reproductive endocrinology, bone biology, thrombosis, and cardiovascular disease in one career generates a depth of cross-system physiological understanding that Arey considers genuinely valuable for drug discovery. He is equally honest that the approach slows career progression - each transition resets the publication clock and delays the depth of specialization that institutional advancement rewards. He made the trade knowingly, and would make it again. In drug discovery, intuition precedes the hypothesis - not the other way around Arey argues that the most significant hypotheses he has generated throughout his career originated in pattern recognition and intuition, before any supporting data existed. He is careful not to overstate this: data drives decisions. But he maintains that the hypothesis itself - the moment where you commit to a direction - comes from something that looks more like a gut feeling than a literature review. For scientists trained to distrust that instinct, it is a useful challenge. Trust is not a leadership style - it is the operating condition for innovative science Running a 70-person research organization, Arey returns repeatedly to trust as the variable that determines whether people bring their actual thinking to the team. Not warmth, not informality - but the concrete belief among scientists that their leader has their interests at heart. He describes this as the only environment in which people are willing to surface the unconventional idea that might be the one that works. Episode Timeline Timestamps are AI-generated from the transcript and may require minor manual adjustment. 01:30 - Returning to the conversation: leading a 70-person organization on an interim basis 03:10 - Leadership style: trust, communication, and creating the conditions for good science 08:58 - The drug discovery process from pathophysiology to target selection 16:49 - Organizational patience and the go/no-go discipline in early discovery 23:09 - GPR56 as a GPCR mechanosensor: knowing the answer before the field did 27:35 - Intellectual humility and the drug discovery team as a problem-solving unit 37:10 - The KLF2 pathway, GPCRs, and atherosclerosis: a program that ended too soon 42:39 - Career breadth across physiology: the advantage and the professional cost 57:50 - Scientific identity, introversion, and putting yourself out there 01:05:19 - Intuition as hypothesis generator: what comes before the data Selected Quotes "There was a paper that came out a couple of years ago on GPR-56, showing that GPR-56 was a mechanotransducer in endothelial cells. And literally, I knew that about 10 years before everybody. That's just the way it goes." "All the key discoveries I've made in my career were based initially on intuition. And then how the puzzle pieces fit together. From there, you use the data to drive whether or not you're correct." "Yeah, it inhibits your career. I will say that." "I've spent 25 years pushing back against that. I feel like as scientists, we should be who we are. Just because I don't act like somebody else doesn't mean I'm not a good scientist. It just means I'm different." About this episode Brian Arey is Senior Director of Mechanistic Pharmacology within Leads Discovery and Optimization at Bristol-Myers Squibb Co . in Lawrenceville, NJ. He obtained both his MS and Ph.D. in Neuroendocrine Physiology at Florida State University before completing his postdoctoral training at Northwestern University. He then moved to work in the pharmaceutical industry where he has held positions of increasing responsibility. He currently leads a team that provides a mechanistic understanding of small molecule drug candidates across the entire portfolio of BMS. Brian has contributed to the discovery or development of 5 marketed drugs through his work spanning molecular, biochemical, cellular, and in vivo assessment of drug candidates in many different physiological systems. Dr. Arey’s laboratory discovered the first described synthetic agonists and antagonists of the FSHR and has been an early champion of signaling bias as a physiological mechanism of gonadotropin action. He continues to pioneer in drug discovery studying GPCRs and other target classes. His recently published book on signaling bias, Biased Signaling in Physiology, Pharmacology, and Therapeutics is available on Amazon . I sat down with Brian to chat about GPCRs, working in the industry, and being a leader. This is part 1 of our conversation. Dr. Brian Arey on the web LinkedIn ResearchGate Pubmed Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

GPCRs drive cancer more often than the textbooks say. Dr. Silvio Gutkind on G protein hotspot mutations, why the canonical GαQ pathway fails in uveal melanoma, and how CXCR3 may gate immunotherapy response. << Back to podcast list Strategic Partner(s) Silvio Gutkind: When GPCRs Drive Cancer GPCRs are the most drugged protein family in medicine, but until recently their role in cancer was treated as marginal — a few curiosities around mas and muscarinic receptors, overshadowed by kinases and Ras. The emergence of cancer genomics has dismantled that framing. Roughly 20% of tumors now show mutations in GPCRs or their coupled G proteins, and specific cancers — uveal melanoma above all — are understood to be driven almost entirely by single hotspot mutations in GαQ. For Dr. J. Silvio Gutkind, who has spent more than three decades pushing GPCRs as oncogenic signaling systems, the shift has concrete stakes: uveal melanoma patients who metastasize to the liver live six to twelve months, and every pathway his lab has opened — from TRIO and Rho to YAP and FAK — has been an attempt to give those patients something the canonical PLC pathway could not. In this conversation, Dr. Gutkind traces how GPCRs moved from a side project nobody believed in to a recognized driver class in oncology, and explains why chemokine receptors like CXCR3 may be the next frontier for understanding immunotherapy response. About the Guest Dr. J. Silvio Gutkind is Professor of Pharmacology and Associate Director of Basic Science at the UC San Diego Moores Cancer Center. His training began at the University of Buenos Aires on alpha-2 adrenergic receptors, continued at the NIH across neurobiology and oncogenes, and grew into a multi-decade program on GPCR signaling in cancer — first as NIH branch chief at NIDCR, then as head of a team that moved cross-country with him to UCSD in 2015. His lab combines classical pharmacology with cancer genomics, bioinformatics, and synthetic lethality approaches to identify druggable nodes downstream of G protein mutations. Current focuses include GαQ-driven uveal melanoma, GαS mutations across pancreatic, colon, and appendix cancers, and chemokine receptor biology in cancer immunotherapy. Scientific Themes of the Conversation GPCRs as oncogenes without mutations — aberrant expression and "oncocrine" autocrine/paracrine signaling The cancer genomics revolution and the rise of G protein hotspot mutations (GαQ Q209, GαS, Gα13) GαQ-driven uveal melanoma and the limits of the canonical PLC pathway Non-canonical GαQ signaling through TRIO, Rho, YAP, and the druggable FAK node CXCR3 and the chemokine axis that gates immunotherapy response Structural biology, machine learning, and team science in GPCR pharmacology Key Insights from the Conversation 1. GPCRs don't need mutations to drive cancer. Aberrant expression — a receptor in the wrong place at the wrong time, paired with autocrine or paracrine ligand — is sufficient to transform cells. Early focus-formation assays using muscarinic receptors and carbachol produced transforming efficiencies comparable to Ras, and the community largely looked away because the biology didn't fit the prevailing mutation-centric frame. 2. Cancer genomics rewrote the role of G proteins. Roughly 20% of tumors carry mutations in GPCRs or G proteins, with striking hotspots in GαQ, GαS, and Gα13. Most large cancer sequencing panels now include these genes — though most oncologists are still unsure what the results mean clinically, leaving a gap between the genomic data and how it's acted upon. 3. The uveal melanoma driver is almost monogenic. Nearly 93% of uveal melanomas carry a single GαQ Q209 activating mutation that blocks GTPase activity. Beyond this driver, the tumor has only a handful of additional mutations — more like a pediatric cancer than an adult one. The canonical assumption that targeting PLC would be therapeutic has failed in the clinic, and patients with liver metastases still have six to twelve months to live. 4. Non-canonical signaling opened a new drug target. A synthetic lethality analysis performed entirely in silico revealed that GαQ tumors depend not only on PLC but on a TRIO → Rho → YAP axis, with FAK emerging as a druggable downstream node. That insight is now powering focal adhesion kinase–directed clinical trials, including one Dr. Gutkind's team is launching. 5. CXCR3 may be the hidden gatekeeper of immunotherapy response. CXCL9, CXCL10, and CXCL11 are among the most robust predictive signatures for checkpoint inhibitor response — and all three are ligands for CXCR3. In knockout mice, loss of CXCR3 abolishes response to both anti-PD-1 and anti-CTLA-4, reframing the receptor as something to activate, not block. 6. "What the heck" moments define real discoveries. Two of Dr. Gutkind's most cited papers came from results that directly contradicted the textbook: βγ subunits (not α) activating ERK through Gi-coupled receptors, and Rho GTPases (not Ras) driving JNK activation. Both required trusting the data when the conceptual framework was telling the team they must be wrong. Both landed in Nature and Cell respectively. 7. Team science is structural, not decorative. The 2020 Cell paper on G protein coupling specificity came from a Gordon Conference hallway conversation, combining bioinformatics from Europe, high-throughput screens from Japan, and biology from UCSD. And the 12 people who moved cross-country from NIH to UCSD did so because of relationships built over years — a retention outcome Dr. Gutkind attributes to the team, not the weather. Selected Quotes "The very simple concept is that GPCRs do not need to be mutated to be oncogenic." "There are cancers that are driven by G proteins. That changed the landscape in terms of understanding and appreciation." "What the heck — this doesn't make sense. And that was our first Cell paper. Still our most cited paper." "Don't be afraid to send emails." Episode Timeline 00:00 Introduction 02:09 From Buenos Aires to NIH: a career that followed the science, not the field 06:19 Operation Exodus — the team that moved cross-country 07:35 The muscarinic focus assay and a side project no one believed in 10:52 The cancer genomics result that reframed GPCRs as drivers 16:45 Why CXCR3 may decide who responds to checkpoint inhibitors 20:28 GαQ, uveal melanoma, and the failure of the textbook pathway 41:27 Structural biology, machine learning, and the coupling problem 45:31 Two "what the heck" moments that became Nature and Cell papers 50:48 Advice for young scientists — read, think, question the dogma 56:33 Why small conferences produce the best collaborations Timestamps were generated using AI for readability. About this episode Have you had moments that defined your scientific tastes? For Dr. J Silvio Gutkind, a class on oncogenes and his interests for GPCRs helped shape his scientific interests. These took him from the University of Buenos Aires in Argentina to UC San Diego and through the National Institutes of Health in Bethesda, Maryland. In this episode, Silvio discusses G protein signaling in the context of cancer, immunotherapies, and combination therapies that could help improve patients’ lives. Dr. J. Silvio Gutkind on the web Dr. J Silvio Gutkind on LinkedIn Gutkind Lab – UC San Diego Moores Cancer Center Gutkind Lab publications Gutkind Lab on Pubmed Gutkind Lab on Twitter UCSD Moores Cancer Center Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Lauren M. Slosky About Dr. Lauren M. Slosky Lauren Slosky is an Assistant Professor in the Department of Pharmacology and a member of the Medical Discovery Team on Addiction, a multidisciplinary initiative within the University of Minnesota’s Medical School to advance research and treatment in the field of drug addiction. Dr. Slosky’s research is focused on understanding how neuropeptide G protein-coupled receptors (GPCRs) regulate motivated behavior and how these receptors can be targeted for therapeutic benefit. Dr. Slosky was awarded a B.S. with honors in Molecular and Cellular Biology and Psychology from The University of Arizona in 2011. She received a Ph.D. in Medical Pharmacology from The University of Arizona in 2015 and completed a postdoctoral fellowship in the laboratory of Dr. Marc G. Caron at Duke University. Dr. Slosky opened her laboratory at the University of Minnesota Medical School in 2021. While a postdoctoral fellow, Dr. Slosky characterized a new class of β-arrestin biased allosteric modulators (BAMs) for the neurotensin receptor 1. These ligands stimulate receptor β-arrestin recruitment without activating canonical G protein signaling. Critically, these ligands reduce addiction-associated behaviors in animal models without the side effects characteristic of balanced receptor activation. Because BAMs engage less well-conserved allosteric sites and exert pathway-specific effects on receptor signaling, they are exciting tools for linking distinct signaling pathways with their physiological effects and may serve as the basis for more selective therapeutics. This work was made possible by the optimization of longitudinal intravenous self-administration paradigms for genetically modified mice. Integrating GPCR biology, behavioral pharmacology, and systems neuroscience approaches, the Slosky Lab is now working to understand how the principles of receptor allosterism and functional selectivity can be leveraged in the development of safe and effective treatments for stimulant and opioid use disorders. Dr. Slosky’s work has been recognized through several travel and research awards, including the William James Psychology Award, the Hank Yamamura Endowed Fellowship in Pharmacology, an NIH F32 Postdoctoral Fellowship, and an NIH K99/R00 Pathway to Independence Award. In addition to research, Dr. Slosky is passionate about training the next generation of scientists and increasing diversity, equity, and inclusion in science. An advocate for trainees at all levels, she served as Service Chairperson and Interim President of the Duke University Postdoctoral Association. She is currently a faculty trainer for the University of Minnesota's MS and Ph.D. programs in Pharmacology, Graduate Program in Neuroscience, and Life Sciences Summer Undergraduate Research Program and is working to build relationships with key stakeholders through institutional and community service. Dr. Lauren M. Slosky on the web Twitter University of Minnesota Department Page LinkedIn Google Scholar PubMed Research Gate Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Cheloha builds nanobody-GPCR ligand conjugates that rescue weak peptides, engineer receptor selectivity, and probe endosomal signaling at NIH. << Back to podcast list Strategic Partner(s) Ross Cheloha: Nanobody-GPCR Conjugates and the Engineering of Receptor Selectivity The parathyroid hormone receptor sits at the intersection of calcium homeostasis, bone metabolism, and a set of pharmacological questions that have resisted clean resolution for decades. How does receptor conformation shape the duration of downstream signaling? Why do some ligands continue activating from the endosome while others don't? And can selectivity for one receptor subtype be engineered without redesigning the ligand from scratch? Ross Cheloha approaches these questions from a chemical biology perspective - using synthetic peptide analogs, camelid single-domain antibodies (nanobodies), and bifunctional conjugates that split the binding event into two independently tunable pieces. In this conversation, he describes how attaching a moderately active peptide to a receptor-targeted nanobody can boost potency by up to 10,000-fold, and how the selectivity of the nanobody - not the ligand - is what engineers receptor subtype specificity. For Cheloha, the motivation traces back to a habit he carried from childhood: writing reports on exotic diseases and what scientists were doing to treat them. The experiment that mattered most was not a drug candidate or a clinical advance - it was a designed conjugate that worked when there was no clear reason it had to, every control behaving exactly as expected. About the Guest Ross Cheloha is a tenure-track investigator at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health. His research combines peptide chemistry, chemical biology, and nanobody engineering to build mechanistic tools for studying GPCR signaling, with a particular focus on the parathyroid hormone receptor and its downstream consequences for calcium homeostasis and bone biology. Trained in the Gelman lab at the University of Wisconsin-Madison and later in the Ploegh lab at Harvard Medical School and Boston Children's Hospital, he developed methods for covalently functionalizing camelid single-domain antibodies with synthetic ligands to probe receptor conformation, endosomal activity, and the duration of signaling responses. His work has demonstrated that nanobody-ligand conjugates can rescue pharmacologically weak peptides, engineer receptor subtype selectivity, and open mechanistic questions that conventional ligand design cannot easily address. Scientific Themes of the Conversation Peptide analog engineering and the stabilization of GPCR ligands using non-natural amino acids Receptor conformation selectivity: G-protein coupled versus uncoupled states and their downstream consequences Camelid single-domain antibodies (nanobodies) as a platform for GPCR chemical biology Nanobody-ligand conjugates as bifunctional tools for potency rescue, selectivity engineering, and mechanistic dissection Duration of signaling and endosomal GPCR activity: what wash-and-measure paradigms have been missing Tissue-specific receptor targeting and the pharmacological logic of reducing GPCR side effect profiles Key Insights from the Conversation 1. Conformation selectivity changes the duration of the signal PTH receptor exists in G-protein coupled and uncoupled states, and peptide analogs incorporating non-natural amino acids show differential affinity for each conformation. The analogs that preferentially bind the uncoupled state produce markedly prolonged signaling responses - in cells and in animal experiments - compared to ligands that do not. The biology may have been using this distinction all along: two natural ligands for the same receptor already show subtly different conformation preferences and different physiological profiles in vivo. 2. One nanobody, four orders of magnitude Connecting a short, weakly active PTH fragment (11 amino acids, approximately 100 nanomolar potency) to a receptor-targeted nanobody produced sub-nanomolar potency in cell-based assays - an improvement of up to 10,000-fold from a single engineering step. The working model is that the nanobody anchors the conjugate at the receptor surface, positioning the ligand for activation that would otherwise be too transient to drive a strong response. The selectivity comes from the nanobody's binding specificity, not from chemical modification of the peptide itself. 3. Selectivity without redesigning the drug PTH 1-34 activates both PTHR1 and PTHR2 with high potency, and engineering subtype selectivity through chemical modification of the peptide is technically demanding. Attaching a short PTH fragment to a PTHR1-selective nanobody produces a ligand selective for that subtype; the same fragment attached to a PTHR2-selective nanobody redirects it entirely. The implication generalizes: wherever a selective nanobody exists for a GPCR target, it can be used to introduce specificity into an otherwise promiscuous ligand without restructuring the pharmacophore. 4. Endosomal signaling is being missed Conventional GPCR assay design - stimulate, wash, measure endpoint - systematically misses signaling that continues after receptor internalization into the endosome. Cheloha's position is that the standard assumption linking tighter binding to longer signaling is incomplete. Endosomal activity is a distinct mechanistic process, and the tools to dissect it - bifunctional conjugates with independently tunable affinity components - are not available with conventional single-piece ligands. This is the central mechanistic priority he is bringing to his NIH lab. 5. Tissue-specific targeting as a strategy for reframing side effects The primary dose-limiting side effect of PTH-based therapies is hypercalcemia, driven in part by receptor activity in kidney tissue rather than bone. Connecting a ligand to a tissue-targeted nanobody could restrict receptor activation to bone and reduce unwanted calcium release. The pharmacological logic is sound, and the engineering framework to test it exists. Whether it holds in vivo remains to be demonstrated - Cheloha is careful to say so - but it represents a genuinely new angle on a long-standing problem in PTH pharmacology. 6. The experiment that had no reason to work - and did Among three scientific aha moments Cheloha described, the one with the clearest forward momentum was the first successful nanobody-PTH conjugate - designed not because a clear rationale existed, but because he wondered whether it was possible. No hypothesis guaranteed the result. Every positive and negative control performed exactly as designed. The conjugate worked. That single experiment, Cheloha said, opened more mechanistic doors than anything he had produced before - and it came directly from experience-built intuition rather than hypothesis-first design. Episode Timeline Timestamps are AI-generated from the transcript and are approximate. Verify against the final edited video before publishing. 00:00 Introduction 01:58 From pharmacy school to chemical biology: how the research path took shape 08:12 Academia versus industry - why freedom to ask non-translatable questions matters 09:43 The academic job search: 65 applications, six interview trips, and landing NIH 14:20 How a peptide chemist found the PTH receptor - and a collaborator who changed everything 17:20 Non-natural amino acids, protease stability, and receptor conformation selectivity 21:40 PTH receptor pharmacology: calcium spikes, bone biology, and why long-acting isn't always better 23:22 A detour into immunology and the discovery of camelid nanobodies 25:45 The first nanobody-GPCR ligand conjugate and an unexpected 10,000-fold potency gain 30:32 Engineering receptor subtype selectivity without redesigning the pharmacophore 36:10 Mechanistic priorities at NIH: endosomal signaling and duration of signaling 40:25 Are GPCRs still a good drug target? Biased agonism, endosomal signaling, and what remains 47:13 Three aha moments: first data, an email from Gardella, and the conjugate that worked Selected Quotes "I just thought of something - hey, I wonder if this would work. There was not necessarily an underlying scientific rationale for trying this. I wasn't thinking this is going to be a new drug. I just thought of something and said, I wonder." "I was convinced that I designed something that worked where it was not at all obvious that it was going to work. And that just opened up so many doors." "I don't think tight binding equals longer signaling is necessarily the whole story. I think in large part it's been missed." "Anything you can contribute to that end is hopefully going to provide a step forward in understanding disease and treating disease. The freedom and creativity - that's what I was really attracted to." About this episode Dr. Ross Cheloha is an Investigator at the National Institutes of Health in the Laboratory of Bioorganic Chemistry in Bethesda, MD, where he started in October 2020. He completed his postdoctoral training at MIT and Harvard Med School in the lab of Hidde Ploegh , where he developed new applications of single-domain antibodies (nanobodies). He earned his Ph.D. in Chemistry at the University of Wisconsin-Madison in the lab of Sam Gellman on the study of analogs of the GPCR peptide ligand parathyroid hormone. Work in his independent laboratory is focused on developing new pharmacological tools via chemistry and protein engineering to interrogate GPCR signaling. Ross and I chatted about his work and transition to an independent investigator; join me to learn more about class B GPCRs and Dr. Cheloha’s work. Dr. Ross Cheloha on the web NIDDK Cheloha Lab Google Scholar LinkedIn Twitter ResearchGate Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Sudha Shenoy About Dr. Sudha Shenoy Dr. Sudha Shenoy is currently an Associate Professor in Medicine & Cell Biology in the Division of Cardiovascular Medicine, Duke University Medical Center. She received her Ph.D. from Oklahoma State University and completed her postdoctoral training with Dr. Robert J. Lefkowitz (Nobel Laureate, 2012) at Duke University. Dr. Shenoy’s postdoctoral research discovered that ubiquitination of mammalian G protein-coupled receptors is a tag for lysosomal degradation, whereas ubiquitination of the adaptor protein, β-arrestin, is a tag for receptor internalization and formation of signaling endosomes. Her laboratory has continued to work on identifying the molecular mechanisms that ascribe ubiquitin code on GPCRs and β-arrestins. Current efforts aim to understand the regulation of GPCR and beta-arrestin signaling in the heart and vascular endothelium by the deubiquitinating enzymes USP20 and USP33. Dr. Sudha Shenoy on the web Duke University Personal Reflections and Words of Wisdom: Story From Dr. Sudha Shenoy LinkedIn Pubmed Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Khaled Abdelrahman, Victoria Rasmussen and Madelyn Moore About Dr. Khaled Abdelrahman " Dr. Khaled Abdelrahman graduated in 2006 with a BSc in Pharmaceutical Sciences from Alexandria University (Egypt) followed by MSc in Pharmacology in the same university that was conferred in 2009. He joined the laboratory of Dr. William Cole at the University of Calgary in 2010 for his Ph.D. where he studied the molecular basis underlying altered cerebrovascular function and blood flow in type 2 diabetes. In 2015, He joined Dr. Stephen Ferguson’s laboratory in the Departments of Cellular & Molecular Medicine and Neuroscience at the University of Ottawa as a Postdoctoral Fellow to explore novel G protein-coupled receptor (GPCR) candidates that can be targeted pharmacologically to slow neurodegeneration. He has been also studying what aspects of GPCR signaling are regulated in a sex-selective manner and how this can influence drug discovery in the area of neurodegenerative diseases. He is also a Registered Pharmacist in Canada and held two of the most prestigious Clinician Postdoctoral Fellowships offered by Alberta Innovates and Canadian Institutes of Health Research. He received the Canadian Society of Pharmacology and Therapeutics Postdoctoral and Publication awards along with many Young Scientist Awards from the American Society for Pharmacology and Experimental Therapeutics. " Dr. Khaled Abdelrahman on the web Twitter PubMed Google Scholar Dr. GPCR About Victoria Rasmussen "Victoria Rasmussen is a graduate fellow in Dr. Thomas Sakmar’s laboratory at The Rockefeller University, where she study’s the signaling and degradation of G protein-coupled receptors. She completed her undergraduate education at Providence College, receiving a B.S. in Biology and a B.A. in psychology. During her time at Providence College, she received the Walsh Grant Fellowship to develop novel methods of synthesizing 2 -imidazoline scaffolds to be used as proteasome modulators in the laboratory of Travis Bethel. Victoria started her Ph.D. at the Tri-Institutional Ph.D. program in Chemical Biology, where she joined the lab of Thomas Sakmar at The Rockefeller University. She is currently working to understand the signaling and degradation of GPCRs in disease states to help test the feasibility of using protein-targeted degradation as a therapeutic strategy. " Victoria Rasmussen on the web Tri-Institutional PhD Program in Chemical Biology Rockefeller University LinkedIn Dr. GPCR About Madelyn Moore "Madelyn (Maddi) earned her B.S. in Biochemistry from the University of Minnesota-Duluth in 2020. In her time as an undergraduate, Maddi was a researcher in Dr. Amanda Klein's lab where she helped to investigate the role of various ATP-sensitive potassium channels in pain and opioid tolerance. From there, she went on to be a research technologist in Dr. Richard Vile's lab at Mayo Clinic where she aided the evaluation of tumor-specific oncolytic viruses. Maddi is currently a second year Ph.D. student in the Molecular Pharmacology and Therapeutics (MPaT) Graduate Program at the University of Minnesota. Advised by Dr. Lauren Slosky, she is working to understand the mechanism by which a new class of biased allosteric modulators for the neurotensin receptor 1 (NTSR1) act to attenuate the behavioral effects of methamphetamine." Madelyn Moore on the web MPaT PubMed LinkedIn Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Juan José Fung About Dr. Juan José Fung Dr. Juan José Fung is a Principal Scientist at GPCR Therapeutics, Inc , a drug discovery company focused on targeting GPCR heteromers in cancer, headquartered in Seoul, Korea, with an R&D facility in the SF Bay Area. Dr. Fung received his Ph.D. from the Stanford University School of Medicine under the mentorship of Dr. Brian Kobilka , studying the dimerization of GPCRs. Dr. Fung continued his Postdoctoral training in Dr. Kobilka’s lab contributing to the elucidation of high-resolution structures of various GPCRs. Dr. Fung has spent significant time in the industry studying membrane proteins, antibodies, and HTS methods for drug discovery. His current work is mainly focused on screening and assay development to bridge the gap between in vitro and in vivo GPCR pharmacology. Dr. Juan José Fung on the web LinkedIn GPCR Therapeutics Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) A Brief History of allosteric modulation with Dr. Arthur Christopoulos About Dr. Arthur Christopoulos " Arthur Christopoulos is the Professor of Analytical Pharmacology and the Dean of the Faculty of Pharmacy & Pharmaceutical Sciences, Monash University, Australia. His research focuses on novel paradigms of drug action at GPCRs, particularly allosteric modulation and biased agonism, and incorporates computational and mathematical modelling, structural and chemical biology, molecular and cellular pharmacology, medicinal chemistry, and preclinical models of behaviour and disease. His work has been applied to studies encompassing neurological and psychiatric disorders, cardiovascular disease, obesity, diabetes, chronic pain and addiction. He has received substantial, long-term support from international and national competitive, charitable and commercial sources, as well as being academic co-founder of three GPCR-focussed biotechnology companies. Professor Christopoulos has over 360 publications, including in leading international journals such as Nature,Science and Cell, and has delivered over 180 invited presentations. He has served on the Editorial Board of 8 international journals and was a Councillor of the International Union of Basic and Clinical Pharmacology (IUPHAR). He has also been the recipient of multiple awards, including the John J. Abel Award and the Goodman and Gilman Award from the American Society for Pharmacology and Experimental Therapeutics; the Rand Medal from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists; the British Pharmacological Society’s Gaddum Memorial Award; the IUPHAR Sir James Black Analytical Pharmacology Lecturer; the GSK Award for Research Excellence and a Doctor of Laws (Honoris Causa) from the University of Athens. Since 2014, Clarivate Analytics have annually named him a Highly Cited Researcher in ‘Pharmacology & Toxicology’, and in 2021 also named him a Highly Cited Researcher in the additional category of ‘Biology & Biochemistry’. In 2017, he was elected a Fellow of the Australian Academy of Health and Medical Sciences, in 2018 as a Fellow of the British Pharmacological Society, and in 2021 he was elected a Fellow of the Australian Academy of Science for his seminal contributions to drug discovery. In 2023, he was elected a Fellow of the Pharmaceutical Society of Australia. " Dr. Arthur Christopoulos on the web Monash University Wikipedia Google Scholar LinkedIn Dr. GPCR AI Summary Quick recap Yamina and Arthur discussed Arthur's career journey in pharmacology, including his mentors and significant discoveries related to allosteric receptors. They explored the evolution of the field, allosteric modulation concepts, and potential therapeutic approaches involving autoantibodies and allosteric modulators. Additionally, they covered the importance of target product profiles, reproducibility in experiments, and collaborative efforts such as a potential book on GPCR history. Next steps - Arthur will continue to collaborate with other researchers and drug companies to advance the understanding and application of allosteric modulation. - Arthur will work on designing ligands for specific receptors, aiming to create biased agonists for therapeutic use. Summary Arthur's Career Journey and Allosteric Receptors Yamina and Arthur discussed Arthur's career journey and his contributions to the field of pharmacology, with a focus on allosteric receptors and their modulation. Arthur highlighted his mentors' influence, such as Fred Mitchelson and Nigel Burch, and significant discoveries like the concept of synthetic allosteric modulators by Bruns and Fergus. He also discussed the evolution of the field, from biochemical radioligand binding assays to cell-based functional assays, and the influence of Terry Kenakin and chemical programs on his later work. The conversation ended with Arthur's ongoing research and his development of a new operational model. Yamina emphasized the importance of understanding the historical context of the field and the significance of Arthur's contributions. Allosteric Modulation and Hybrid Molecules Arthur and Yamina discussed the development of an operational model for allosteric modulation, emphasizing the balance between mechanism and empiricism. Arthur shared his career journey, including his collaboration with Patrick Sexton and Jim Burch, and the discovery of hybrid molecules with functional selectivity. They also discussed the re-emergence of interest in certain programs, the importance of connections across receptor families, and the potential of hybrid molecules. Arthur's strategy of consulting drug companies and targeting their posters at conferences was also shared with Yamina. Pharmaceutical Industry Experiences and GPCR History Arthur shared his experiences in the pharmaceutical industry, highlighting the differences between big pharma and biotech. They discussed strategies for analyzing large compound screening data, emphasizing robust assays and addressing issues like shifting curves. Arthur recounted a 2004 visit to a pharma company using replicates in assays. Yamina proposed compiling a book on GPCR history through collaborative interviews, considering a symposium to align terminology. For their upcoming project, Yamina favored a conversational approach, while Arthur suggested a kickoff meeting, with Yamina planning chapters and interviews. Bias Mitigation in Symposium Ideas Arthur and Yamina discussed the concept of bias in the context of the history of the Symposium idea. They reviewed significant early papers related to the topic, including work by Brian Roth, Terry Kenakin, Bill Clarke, and Kelly Burke. They also discussed their own research on chemokine receptors and the importance of understanding the natural environment in drug discovery. Lastly, they touched on a project with Nicola Smith that challenged their previous theories. Allosteric Modulation and Drug Discovery Yamina and Arthur delved into the complexities of protein-protein interactions, specifically allosteric modulation. They discussed various modulatory elements, such as RAMPs, G proteins, and GRKs, with Arthur recounting his initial collaboration with Patrick Sexton on RAMPs and amylin receptors. They also delved into the different signaling of Class B receptors and the potential for modulation at various levels. The discussion underscored the potential of allosteric modulators as drugs, despite challenges in the past due to a lack of understanding about the principles involved. They highlighted the importance of fine-tuning the approach to suit different diseases and interdisciplinary collaboration. The discussion also emphasized the need for a disease-specific approach, considering the clinical context and dialing in the desired effect, as well as the significance of rational drug design principles. Allosteric Modulation and Autoantibodies Discussion Arthur and Yamina discussed the potential of autoantibodies and allosteric modulation in the context of disease and therapeutic approaches. Arthur explained the concept of endogenous allosteric ligands and the possibility of using a neutral allosteric ligand as a preferred therapeutic approach, emphasizing the importance of looking for low level cooperativity factors. They also discussed the potential of certain drugs, like flumazenil, as 'nails' or compounds that could be developed into medicines. The conversation highlighted the importance of establishing the correct disease context, setting up appropriate assays, and understanding the models for their work. They both agreed on the necessity of understanding the target product for an allosteric modulator and working backwards from there. TPP, Allosteric Modulators, and Reproducibility Yamina and Arthur discussed the concept of a target product profile (TPP) in drug development, with Arthur explaining its application in other contexts as well. Yamina appreciated Arthur's expertise and indicated she would be creating an outline for an episode on allosteric modulators. They highlighted the importance of reproducibility in scientific experiments, sharing personal experiences and anecdotes. They also discussed their upcoming trips to the GPCR Colloquium in California and current research in their fields. Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. 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<< Back to podcast list Strategic Partner(s) Dr. Kenneth A. Jacobson About Dr. Kenneth A. Jacobson Kenneth A. Jacobson received his BA in Liberal Arts from Reed College in 1976 and his Ph.D. in Chemistry from the University of California, San Diego in 1981. He completed postdoctoral training at the Weizmann Institute. In 1983, he joined the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health, in Bethesda, MD. He is currently the Senior Investigator and Chief of the Molecular Recognition Section, Laboratory of Bioorganic Chemistry. He adapts interdisciplinary approaches (synthesis, modeling, pharmacology) to study G protein-coupled receptors (GPCRs) and purinergic signaling and now has four compounds in clinical trials. He has published more than 800 scientific publications, with an H-index of 115. His numerous awards include: 2008 Sato Award; 2009 Medicinal Chemistry Hall of Fame (American Chemical Soc.); 2014 Goodman and Gilman Award; 2017 Tu Youyou Award; 2017 Smissman Award; 2023 Hershberg Award. Dr. Kenneth A. Jacobson on the web NIDDK Web of Science Google Scholar LinkedIn Twitter Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. G. Aditya Kumar About Dr. G. Aditya Kumar Dr. Aditya Kumar is a postdoctoral fellow at the University of Michigan Medical School. Aditya is interested in understanding the role of the membrane microenvironment in the subcellular organization, trafficking, and signaling of GPCRs. He received his Ph.D. from the Centre for Cellular and Molecular Biology at Hyderabad, India, where he studied the interaction of membrane cholesterol with the serotonin-1A receptor and its effects on receptor signaling and endocytosis. In addition, he explored the role of the host membrane in the entry of intracellular pathogens into macrophages. He currently uses high-resolution fluorescence microscopy and biochemistry to study GPCR trafficking mechanisms. In his (future) independent research career, Aditya aims to work at the interface of GPCR molecular pharmacology, subcellular trafficking, and membrane biology to better understand how the dynamic receptor microenvironment contributes to GPCR organization and function. Dr. G. Aditya Kumar on the web University of Michigan Puthenveedu Lab Google Scholar NIH ORCID LinkedIn Twitter Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Christel Menet About Dr. Christel Menet "I did my Ph.D. in Manchester UK with Prof Jonathan Clayden in organic chemistry. I then started my career at Evotec before moving to Domain Therapeutics (called Faust pharmaceutical at the time). After 2 years, I joined Galapagos where I spent almost 11 years and became head of medicinal chemistry. 6 years ago I decided to take on a new challenge by taking the position of CSO at Confo Therapeutics . I was the 6th employee and today we are more than 60 :) I have fun every day, and I love working with GPCRs. they are such great targets." Dr. Christel Menet on the web Hyphen Projects GPCRS Drug Discovery Confo Therapeutics LinkedIn Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Martin Audet About Dr. Martin Audet Structural biologist, pharmacologist, and a professor of pharmacology at Université de Sherbrooke. He is the head of the AudetLab located at the Institute of Pharmacology of Sherbrooke and is an emerging leader in the structural biology of G Protein-Coupled Receptors and passive transporters. Strong education with a Doctor of Philosophy (Ph.D.) in biochemistry under the supervision of Michel Bouvier at Université de Montréal, followed by a Postdoctoral Fellow at Scripps Research in San Diego and the University of Southern California in Los Angeles as a member of Raymond Stevens group. Dr. Martin Audet on the web LinkedIn Twitter Sherbrooke University Google Scholar Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

How a bell-shaped FSH dose-response curve led to one of the earliest demonstrations of biased GPCR signaling - and a decade of pushback from the field. << Back to podcast list Strategic Partner(s) Brian Arey: Discovering Signaling Bias at the FSH Receptor Biased signaling - the idea that a single receptor can preferentially activate one downstream pathway over another depending on how it is engaged - is now a central concept in GPCR pharmacology and drug design. But for the researcher who first encountered it not as a theory but as an anomalous bell-shaped dose-response curve in an FSH receptor assay, it arrived as a problem that needed explaining. Brian Arey, Director of Mechanistic Pharmacology at Bristol-Myers Squibb, traces the origins of that discovery to a glycosylation difference between pituitary-purified and insect-cell-expressed FSH - a difference that turned out to encode physiologically distinct signaling outputs. The broader argument Arey has spent his career developing is that biased signaling is not a GPCR-specific phenomenon but an evolutionarily conserved principle present across all receptor classes. That argument eventually became a book, co-authored with Terry Kenakin, that Arey dedicated to his children - not because they are scientists, but because he wanted them to understand what he spent his life doing and why it mattered. ABOUT THE GUEST Brian Arey is Director of Mechanistic Pharmacology within the Discovery and Optimization organization at Bristol-Myers Squibb, where he leads research spanning GPCR pharmacology, enzymology, and protein homeostasis pathways. A physiologist by training, he completed his doctoral work on circadian regulation of prolactin secretion at Florida State University before postdoctoral research at Northwestern, and has spent over 25 years in pharmaceutical drug discovery across Wyeth and BMS. His early work at Wyeth's Women's Health Research Institute produced foundational observations on biased signaling at the FSH receptor, which were among the first experimental demonstrations that a GPCR could signal through parallel G protein pathways in a ligand-dependent manner. He is the author of a 2014 book on evolutionarily conserved receptor signaling, co-written with Terry Kenakin and published through Elsevier. SCIENTIFIC THEMES OF THE CONVERSATION Biased signaling at glycoprotein hormone receptors - the experimental origin Glycosylation isoforms as physiological regulators of differential receptor signaling Evolutionary conservation of biased receptor function across receptor classes The physiologist's approach to mechanistic drug discovery The erosion of pharmacology training in pharmaceutical research - and why it matters Career navigation across academia, industry, and the blurring boundary between them KEY INSIGHTS FROM THE CONVERSATION The bell-shaped curve was a hypothesis, not an artifact When insect-cell-expressed FSH produced a bell-shaped dose-response curve instead of a sigmoidal one, the obvious interpretation was contamination or a production problem. Arey treated it as a signal. The glycosylation difference between the recombinant material and pituitary-purified FSH had altered the receptor's downstream signaling profile - and the bell shape was the read-out. It took a pertussis toxin experiment, borrowed conceptually from Tom Burris's dopamine receptor work, to demonstrate that FSH receptor was signaling through both Gs and Gi simultaneously, and that the two glycoforms were biasing the system differently. Forty years of unresolved biology had a signaling answer The existence of multiple glycosylated isoforms of FSH, LH, and other glycoprotein hormones had been recognized for decades, but their physiological significance was not understood. Arey's data offered a functional explanation: different glycoforms stabilize different receptor conformations, which recruit different intracellular effectors with different affinities, driving different physiological outcomes in target cells. What had looked like biochemical noise in circulating hormone pools was, in this framework, a mechanism for fine-tuned signaling control. If the controls are right, the data has to be trusted When a substantial portion of the literature responded to Arey's published data by calling it wrong, he called his graduate advisor. The advice he received - that if all controls have been run appropriately and the result still holds, you have to have confidence in your data - has remained his operating principle for three decades. That conviction did not resolve the argument quickly. The field took nearly a decade to come around. But the data held. Biased signaling is not a GPCR specialty - it is a conserved principle The central argument of Arey's 2014 book is that the bimodal structure of receptor signaling - a ligand-binding pocket with one inherent affinity, and a cytoplasmic effector-binding pocket with its own independent affinity, both modulated by the conformational state the ligand stabilizes - is not unique to GPCRs. The same logic applies to cytokine receptors, nuclear hormone receptors, and receptor tyrosine kinases. Arey arrived at this hypothesis in the mid-1990s, before the structural and mechanistic data existed to support it, and spent years watching the field gradually produce that evidence. Techniques are tools in a toolbox - not endpoints One of the formative intellectual influences Arey credits from his graduate training is the principle that no technology is intrinsically interesting - it is only interesting insofar as it can answer a scientific question. That orientation shapes how he runs his team at BMS: a healthy skepticism toward established methods, including antibody-based assays that he views as 50-year-old technology capable of improvement, and a standing question of whether the current tool is actually capturing the biology being studied. Drug discovery needs modulators more than it needs hammers Arey's philosophy of drug discovery is grounded in a view of human physiology as inherently variable - shaped by evolution, divergent across populations, and rarely susceptible to single-target solutions. He argues for a therapeutic strategy built around modulators that can be combined, rather than single agents designed to dominate a pathway. That argument is not abstract: it is the conclusion of someone who has watched large programs fail to find silver bullets in multifactorial diseases for 25 years. EPISODE TIMELINE Timestamps are AI-generated from the transcript and may not perfectly reflect final edited audio. Verify against the published episode before using for navigation. 00:00 Introduction 01:48 Career overview - 25 years in drug discovery at Wyeth and BMS 06:03 Origin story - glassware, the first binding assay, and the decision not to become a physician 11:54 Graduate school - independently discovering a circadian rhythm regulating prolactin secretion still cited 30 years later 17:57 Leaving academia for Wyeth - a two-week decision, $18,000 a year, and the door that closed behind it 19:55 The FSH receptor anomaly - how a production shortcut produced the first experimental evidence of biased GPCR signaling 23:40 When the literature called the data wrong - holding the line for nearly a decade 30:41 The physiologist's lens - why Arey has never chased the trending field 35:00 Science, family, and the years he was a single father of two young children 40:35 Writing the book with Kenakin - the argument that biased signaling is evolutionarily conserved, and why he chose a book over a review 48:09 Dinner with Martin Rodbell - drawing the FSH data on a napkin and hearing "I'm not surprised" 53:07 Advice for scientists - follow the data, trust your controls, stay humble, give back 01:01:55 What pharmacologists bring to drug discovery that nobody else does SELECTED QUOTES "If you've done all the controls appropriately, and you've done the experiments to the best of your ability, and you've asked all the hard questions and you still get the same result, then you have to have confidence in your data." "What we study in pharmacology, whether it's a GPCR or whatever, what we're really studying is evolution at the base level. And when you think about it from that perspective, it's hard not to be awed by nature." "I'm not surprised." - Martin Rodbell, upon being shown Arey's FSH signaling data drawn on a dinner napkin, citing a 1972 paper in which Rodbell had proposed a similar mechanism. "Science is really a personal endeavor - it's creative and personal. I hate to say it because it's so overused, but it really is an art form and everybody approaches it differently." About this episode Brian Arey is Senior Director of Mechanistic Pharmacology within Leads Discovery and Optimization at Bristol-Myers Squibb Co . in Lawrenceville, NJ. He obtained both his MS and Ph.D. in Neuroendocrine Physiology at Florida State University before completing his postdoctoral training at Northwestern University. He then moved to work in the pharmaceutical industry where he has held positions of increasing responsibility. He currently leads a team that provides a mechanistic understanding of small molecule drug candidates across the entire portfolio of BMS. Brian has contributed to the discovery or development of 5 marketed drugs through his work spanning molecular, biochemical, cellular, and in vivo assessment of drug candidates in many different physiological systems. Dr. Arey’s laboratory discovered the first described synthetic agonists and antagonists of the FSHR and has been an early champion of signaling bias as a physiological mechanism of gonadotropin action. He continues to pioneer in drug discovery studying GPCRs and other target classes. His recently published book on signaling bias, Biased Signaling in Physiology, Pharmacology, and Therapeutics is available on Amazon . I sat down with Brian to chat about GPCRs, working in the industry, and being a leader. This is part 1 of our conversation. Dr. Brian Arey on the web LinkedIn ResearchGate Pubmed Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Timo De Groof About Dr. Timo De Groof Dr. Timo De Groof studied Biochemistry and Biotechnology at the University of Ghent where he graduated in 2015. During his master's studies, he specialized in Biomedical Biotechnology and Structural Biology/Biochemistry. During his last year of studies, Timo performed research in the biopharmaceutical company Argen X and gained experience in the identification and characterization of llama-derived antibodies in inflammatory diseases and oncology. From 2015 to 2019, he completed his Ph.D. in the Medicinal Chemistry group at VU University Amsterdam under the supervision of Prof. Dr. Martine Smit . During his Ph.D., Timo, together with Dr. Raimond Heukers , developed a nanobody platform within the research group and used this platform to develop nanobodies targeting viral G protein-coupled receptors with a special focus on the human cytomegalovirus-encoded chemokine receptor US28. During his Ph.D., he used these nanobodies as research tools, to investigate different GPCR conformations, while also focusing on their therapeutic potential in oncology and transplant infectious disease. Starting from September 2019, Timo started working as a postdoctoral researcher at the Vrije Universiteit Brussel in the In Vivo Cellular and Molecular Imaging (ICMI) group that is focused on translational/clinical applications of nanobodies. He currently is focusing on the development of nanobody-based immuno tracers as part of the IMI/EFPIA project entitled "Immune Image". Moreover, he is closely involved in multiple projects where he focuses on the generation of nanobodies against "difficult-to-target" proteins. In the near future, Timo hopes to combine his previous GPCR experience with his current focus to set up his own research line focusing on translational applications of GPCR-targeting nanobodies. Dr. Timo De Groof on the web LinkedIn Researchgate Twitter Medical Imaging Group Google Scholar Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Dr. Alex Serafini shares why pain research must start with real-world behavior and models before drilling into GPCR targets — a top-down rethink for drug discovery. << Back to podcast list Strategic Partner(s) GPCRs and the Science Behind Pain and Recovery with Dr. Alex Serafini Strategy: From Personal Pain to Scientific Purpose Dr. Alex Serafini’s entry into science wasn’t typical. Born in California, raised in Silicon Valley, and initially eyeing finance, his trajectory took a sharp turn after struggling with unresolved, chronic pain following repeated surgeries for a pilonidal cyst. "I wasn't able to get stronger pain meds because of the opioid epidemic," he recalls. That gap in care sparked a curiosity that became a career. Driven by personal experience and a desire to innovate in pain management, Alex pursued a master's in pain research at Hopkins and later an MD-PhD at Mount Sinai. His early exposure to TRPV1 channels and peripheral pain mechanisms with Dr. Mike Caterina laid the foundation. But the deeper mission? Finding answers for patients society often overlooks. Pain became more than biology — it became a personal strategy. “I started going through what I was going through… and that got me very interested in research.” — Alex Serafini Decision-Making: Saying Yes to the Unorthodox Path Serafini’s journey defied traditional checklists. He joined Mount Sinai through FlexMed — bypassing the MCAT — and was torn between a career in pharma and academia. At one point, he had a job offer at Roivant (a biotech firm known for repurposing shelved compounds), but a late-stage offer into an MD-PhD program — and parental “encouragement” — rerouted his path. His approach to decision-making is pragmatic: follow impact, not orthodoxy. The decision to stay on as a postdoc in the same lab as his PhD — with Dr. Venetia Zachariou — wasn't the typical next step, but it allowed him to wrap up high-impact work and learn about PI-level grant writing, strategy, and lab management. In his words: “She let me run projects like a junior PI.” “I didn’t need to chase new techniques — I needed to finish the science that mattered.” — Alex Serafini Blind Spots: The Underestimated Role of RGS Proteins in Pain Although not a self-proclaimed GPCR specialist, Serafini found himself repeatedly drawn to them, or more precisely, to RGS (Regulators of G protein Signaling) proteins. The lab’s work with RGS4 led to unexpected results: knockout mice spontaneously recovered from chronic pain after three weeks, an effect rarely observed. He points out that GPCRs—especially orphan and CNS-associated ones—are often downplayed in pain research, with most focus on ionotropic targets like NAV1.8. But Serafini believes that’s a blind spot. “We’re using outdated drugs. There are more elegant GPCR targets waiting to be explored.” The lab’s unconventional in vivo-first strategies, combined with RNA-seq and behavioral analysis, revealed nuanced roles of RGS4, RGS9, and RGSZ — not just as modulators but as potential therapeutic linchpins. “Half the time, in pain, what works in vivo doesn’t translate to clinic. We need new thinking.” — Alex Serafini Failure & Frustration: From Pipettes to Pandemic Disruption The road hasn’t been smooth. From struggling to grip mice in early animal studies to thesis delays during COVID-19, Serafini's journey is marked by grit. But it’s in these friction points that new insights emerged. The pandemic disruption, for instance, led him to BSL-3 labs to study persistent pain after SARS-CoV-2 infection, revealing novel immune-neuron signaling in DRGs. He also opens up about the emotional and logistical toll of MD-PhD training. It’s an eight-year-plus haul with built-in uncertainty. However, with mentors who believed in him, especially those who shared administrative, grant-writing, and leadership skills early on, he found direction and resilience. “She [Vanna] gave me a crash course in what it’s like to be a junior PI. That changed everything.” — Alex Serafini Pivoting: Redefining the Pain Research Playbook Looking ahead, Serafini’s vision is bold: build a lab that develops translational models of pain rooted in patient realities. He’s fascinated by transgenerational epigenetics — how parental pain, diet, or drug exposure can leave molecular fingerprints in offspring. He's equally focused on sex differences in pain processing and the failure of "one-size-fits-all" models in pharmacology. His advice? Learn broadly. Stay close to patients. Collaborate relentlessly. And above all, don’t be afraid to start from the phenotype and work backwards to the mechanism. That top-down approach, though less common, could help pain research finally catch up with the complexity of real-world biology. “Start from the end — from the clinic — and then build backwards.” — Alex Serafini Key Takeaway Innovation in pain research won’t come from doing the same things better — it’ll come from flipping the script. Whether it’s challenging legacy targets, redefining preclinical models, or exploring the epigenetic inheritance of pain, Dr. Serafini urges the field to stay bold, patient-centered, and GPCR-aware. About Alex Serafini Alex was born and raised in the Bay Area and received his BS/MS Neuroscience from Johns Hopkins. His master's degree was in Dr. Michael Caterina's lab studying the role of PNS chloride transporters in neuropathic pain. Upon matriculating to Mount Sinai's MD/PhD program, he joined Dr. Venetia Zachariou's lab to study the effects of chronic pain and addiction/withdrawal on the mesocorticolimbic system, focusing on transcription factor and RGS protein maladaptations, behavioral RGS protein drug "screening", and the role of SARS-CoV-2 on CNS function and sensory hypersensitivity. He aspires to become a physician-scientist, with a focus on translational in vitro and in vivo model development for studying chronic pain and affective comorbidities. Other academic interests of his include studying pharmaceutical finance & healthcare administration and developing technologies that increase healthcare access. His non-academic interests include traveling, scouting out micro-breweries, and collecting beer cans. Alex Serafini on the web LinkedIn Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Elva Zhao on biased agonism at the GLP-1 receptor, G protein regulation, and building a mechanistic picture of GPCR pharmacology from the inside out. << Back to podcast list Strategic Partner(s) Elva Zhao: G Protein Regulation and Biased Signaling at the GLP-1 Receptor The GLP-1 receptor is among the most clinically validated targets in metabolic disease - yet the signaling logic separating the therapeutic benefit of existing drugs from their adverse effects remains poorly resolved. At the center of that problem is biased agonism: the differential engagement of downstream pathways by distinct ligands acting at the same receptor. Understanding which transducer coupling events produce glucose-lowering efficacy and which drive the GI side effects that limit GLP-1 agonist use demands a mechanistic account of receptor-G protein engagement and its regulation. Elva Zhao brings an unusual vantage point to that question. Her PhD at Western University focused not on receptors but on G protein cycle regulation - RGS proteins, GoLoco proteins, and the kinetics of GTP binding and hydrolysis. That training, initially set aside during postdoctoral work on biased agonism at Monash, is now being reintegrated deliberately. Her current research asks how the regulatory proteins that most GPCR pharmacologists have not yet addressed actually shape signaling output at one of the field's most important therapeutic targets. The connection runs deeper than science: Zhao's grandmother worked as a pharmacologist on diabetes in China - decades before her granddaughter would begin studying the receptor that now defines modern diabetes pharmacotherapy. About the Guest Elva Zhao is a Research Fellow at the Monash Institute of Pharmaceutical Sciences (MIPS), Drug Discovery Biology, in Melbourne, Australia. She completed her PhD at Western University, Canada, under Prof. Peter Chidiac, where her work focused on the kinetic regulation of G protein cycling by RGS proteins and GoLoco motif-containing proteins. She subsequently joined MIPS for postdoctoral training, working first with Prof. Nigel Bennett on biased signaling at the PAR2 receptor, then with Profs. Denise Wootten and Patrick Sexton on class B GPCR pharmacology and biased agonism at the GLP-1 receptor. Her current research integrates both frameworks - examining how the GLP-1 receptor engages its transducer partners and how G protein regulatory proteins shape downstream signaling in a physiological context. Scientific Themes of the Conversation G protein cycle regulation and the kinetic roles of RGS and GoLoco proteins Biased agonism at class B GPCRs - ligand-dependent pathway selectivity at the GLP-1 receptor Transducer coupling as the missing mechanistic layer in GLP-1 receptor pharmacology The expanding therapeutic profile of the GLP-1 receptor - from diabetes and obesity to neurodegeneration How collaborative, GPCR-focused research environments change what questions are askable Scientific identity across discontinuous environments - building a research program across three countries and multiple pharmacological frameworks Key Insights from the Conversation 1. The G Protein Regulatory Layer GLP-1 Research Has Not Yet Addressed The pharmacological characterization of GLP-1 receptor agonists has concentrated on receptor-level biased signaling - which downstream pathways are activated - while the proteins that regulate G protein cycle kinetics have received almost no attention in this context. Zhao's research begins to ask what RGS proteins and GoLoco proteins do to modulate the functional output at this receptor, and whether that regulatory layer contributes to the therapeutic window problem that GLP-1 drug development has not solved. 2. Why GLP-1 Drugs Still Produce Nausea - and What Biased Signaling Might Fix The GI side effects of GLP-1 receptor agonists - primarily nausea and vomiting - remain among the main barriers to broader clinical use and optimal dosing. Zhao describes how the objective of biased agonism research at the GLP-1 receptor is to develop ligand profiles that preserve glucose-lowering efficacy while decoupling the pathways driving adverse effects. Executing that requires knowing, with mechanistic precision, which coupling events map to which clinical outcomes. 3. The Scientific Circle Nobody Plans For Zhao's PhD - focused entirely on G protein regulation without studying a receptor - appeared to be a separate chapter from her postdoctoral work on receptor pharmacology and biased agonism. A decade later, she is deliberately bringing both ends of that arc together. The insight that G protein regulatory proteins may shape the functional selectivity of GLP-1 agonists in a physiological context is not a planned convergence - it is the result of building two skill sets sequentially and eventually recognizing that neither was complete without the other. 4. GLP-1 Receptor as a Window Into Neurodegeneration Beyond its established roles in glucose homeostasis and body weight regulation, emerging evidence points to a role for GLP-1 receptor signaling in Parkinson's disease and Alzheimer's disease. Zhao describes how this expanding target profile changes the stakes of understanding how the receptor works - not only in pancreatic beta cells and the periphery, but in neural tissue, where the downstream consequences of biased coupling may differ substantially. 5. What a GPCR-Only Environment Makes Possible The move from a broad pharmacology department in Canada to the GPCR-focused, shared-space environment at MIPS was scientifically consequential for Zhao. Working alongside structural biologists, computational pharmacologists, and receptor scientists working across GPCR classes gave her the methodological range to ask questions she could not have formulated in a more siloed setting - and access to expertise she could find simply by walking to the right floor with a laptop. 6. Following the Question, Not the Credential Zhao describes her decision to pursue a postdoc as emerging from a straightforward observation: there was still a question she wanted to answer. Her mentor, Peter Chidiac, had consistently avoided steering her toward a predetermined career path, asking instead which question she most wanted to work on. That framing - orienting around the scientific problem rather than the next credential - organized each subsequent move she made, from Western to Monash, and from G proteins to receptors and back again. 7. The International Student Trap - Nodding Yes When You Don't Understand One of the frankest passages in the conversation concerns the habit of nodding along when a supervisor is speaking and nothing has been understood - a pattern Zhao describes as nearly universal among international PhD students. The forces behind it are layered: language barriers, cultural conditioning around deference, the general insecurity of early-stage training, and the fear of appearing incompetent. The correction, for Zhao, came slowly - driven by a mentor patient enough to make asking safe, and by the unavoidable evidence that unacknowledged confusion produces problems on both sides of the relationship. Episode Timeline Timestamps are AI-generated from the transcript and are approximate. Minor offsets may occur. 00:00 Introduction and Dr. GPCR Virtual Cafe announcement 01:49 Zhao's scientific background - from Shanghai to Western University 06:49 First contact with G proteins - the muscarinic receptor as a tool, not a subject 09:17 From China to Canada - the international student experience and the language gap 15:09 The mentor who made it safe to say "I don't understand" 19:38 Why Australia - how a single conference in Melbourne redirected the next chapter 22:28 The decision to pursue a postdoc - following the question before you hate the science 28:46 Life at MIPS - collaborative, GPCR-focused, and unexpectedly open 32:30 From PAR2 to GLP-1 - building the mechanistic picture one step at a time 37:01 GLP-1 receptor biology - diabetes, obesity, and the emerging neurodegenerative angle 38:50 Why GLP-1 drugs still need improvement - the side effect problem 41:39 Work-life balance - running, Tilly, and what burnout taught about efficiency 52:58 COVID as unexpected space to think, organize data, and build collaborations 57:58 Advice for trainees - staying curious, knowing your question, and talking to people Selected Quotes "I want to know more of how it's regulated, but I want to know more of upstream. I want to know how the G protein got activated. So receptor is a natural choice." "I feel like I'm not finished yet with answering my own question. And also, I'm fresh out of PhD. I don't hate science yet. So why not do a little bit more?" "On the good day - relatively okay day - I always remind myself of the not so good days, thinking that, okay, I've been there but I'm here now, so I can do this thing." "Keep the core to what is the question that you want to answer. Don't try to be distracted by needing a big paper. Always just keep the core." About this episode Elva is currently a research fellow at the Monash Institute of Pharmaceutical Sciences. Elva moved to Canada where she obtained her Ph.D. at the University of Western Ontario, working on the regulation of G proteins signaling by accessory proteins, such as RGS proteins and GPSM proteins. After her Ph.D., she moved to Australia and continues working on GPCRs. Her current research focuses on class B GPCRs and understanding how GPCR signaling and function is mediated by various ligands, binding partners, and intracellular machinery. In her spare time, Elva likes to run in the mountains, play with Tilly (a 9-year old retired greyhound), collecting mini shoes, and hang out with friends. Join me to learn more about Elva, class B GPCRs, and Tilly. Dr. Elva Zhao on the web LinkedIn Monash University Pubmed Twitter Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. 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<< Back to podcast list Strategic Partner(s) Dr. Bianca Plouffe About Dr. Bianca Plouffe Dr. Bianca Plouffe obtained her B.Sc. in Biochemistry in 2003 from Université de Sherbrooke (Qc, Canada). She then completed an M.Sc. in Physiology from the same university in 2005 by investigating the molecular mechanisms involved in the angiotensin type 2 receptor (AT2R)-mediated neurite outgrowth while characterizing new selective AT2R agonists. In 2006, Bianca obtained a Doctoral Scholarship from the Fonds de Recherche du Québec en Santé. She moved to the University of Ottawa to complete a Ph.D. in Neuroscience. She identified the molecular mechanisms involved in the opposite regulation of dopamine D1 and D5 receptors by protein kinase C. After obtaining a Postdoctoral Fellowship from the Canadian Institutes of Health Research in 2012, Bianca joined the research group of Prof Michel Bouvier at Université de Montréal. As part of Bouvier’s team, Bianca used Bioluminescence Resonance Energy Transfer (BRET)-based technology to tackle important questions related to GPCRs. She identified the structural determinant controlling biased signaling of melatonin type 2 receptors in the context of protection against type 2 diabetes. Bianca also collaborated with Prof. Robert Lefkowitz , which led to the finding that both β-arrestin and G protein can simultaneously bind to some GPCRs when signaling in endosomes by forming a megaplex. In 2018, Bianca was appointed Vice-Chancellor’s Fellow at Queen’s University Belfast to develop her research program. Funded by a Wellcome Trust Seed Award, she investigated biased and compartmentalized G protein signaling by the vasopressin type 2 receptor. In 2021, Bianca secured a permanent position as a lecturer. Her subsequent work has focused on understanding the role of compartmentalized Gq signaling by the cytomegalovirus-encoded chemokine US28 receptor in the context of glioblastoma. Dr. Bianca Plouffe on the web Queen's University Belfast website LinkedIn ResearchGate ORCID Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

Explore the world of GPCRs with Dr. GPCR Podcast! Join industry leaders as they share insights, stories, and groundbreaking discoveries, enriching our understanding of GPCRs. Delve into the science behind these vital components shaping our collective knowledge. Welcome to the Dr. GPCR Podcast - The Voice of the Community Conversations with the world’s leading GPCR scientists. Exploring discoveries, careers, and ideas shaping human health. In each episode, we sit down with leading experts to explore their career journeys, groundbreaking discoveries, and the impact of their research on our shared understanding of GPCR biology. Launched at the height of the pandemic, the Dr. GPCR Podcast was created with three goals: Share discoveries – Highlight the latest advances in the GPCR field. Amplify voices – Provide scientists a platform to showcase their work. Inspire the future – Motivate the next generation to pursue GPCR research. At its core, Dr. GPCR’s mission is simple yet ambitious: to bring the GPCR community together - across borders and disciplines - to connect, exchange, and collaborate in order to improve human health through a deeper understanding of GPCR biology. Latest Podcast Episodes More podcast episodes Dr. GPCR Podcast Audience Survey We are currently planning our next season and need your help. This short survey will help us understand your needs to bring you exciting and informative content. We also know that you are busy, which is why we designed this short survey that should take you 5 minutes. Fill out this form Be our Guest In each episode, we chat with an expert about their career trajectory, discoveries, and how their research contributed to the shared pool of knowledge about GPCR biology. We’d love to have you on our podcast. To be a guest, fill out the form below, and we’ll be in touch in 48 hours. Fill out this form What others are saying about this podcast "You made it a very comfortable and engaging experience, and it felt like we were chatting over coffee — Yamina thoughtfully guided our chat throughout." Anita Nivedha I think it's really well done. I'm genuinely interested to see how it evolves and grows over time, as I feel it has the potential to develop into something even more impactful. Anonymous This came at just the most perfect time. I hadn't heard a scientific talk outside my lab since February and was starved to hear someone else talk passionately about GPCRs. I've listened to the episodes multiple times and it's just like being at a conference getting new ideas. I just couldn't be happier y'all created this podcast. Anonymous Great initiative, thanks. Carrier paths, choosing research topics, switching fields, late start, failures and successes. Anonymous I enjoy the breadth of questioning that goes beyond just the science, and reveals a bit about the scientists as individuals/mentors/people. Anonymous Really enjoyable science podcast! Dr. Yamina Berchiche interviews leading GPCR scientists on this vibrant, entertaining podcast. I really appreciate the way the podcast educates and mentors, particularly towards junior scientists but also to the community as a wholen Yamina is a great interviewer, getting insight and personal history from her guests. Am very grateful for Dr GPCR livening up the week in these difficult times! Sam @Pharmamechanic Listen and subscribe where you get your podcasts

<< Back to podcast list Strategic Partner(s) Dr. Robert F. Bruns About Dr. Robert F. Bruns Fred Bruns discovered the first positive allosteric modulator (PAM) of a GPCR in the late 1980s while working at Warner-Lambert/Parke-Davis. The work was published in 1990. After 7 years at WL/PD and 26 years at Eli Lilly & Co., he retired at the end of 2014 and since then has been writing papers on his final major project at Lilly, a dopamine D1 PAM series that has advanced through Phase 2 clinical trials. Fred obtained an A.B. in Psychology from Washington University in St. Louis, followed by a Ph.D. in Neurosciences at the University of California, San Diego. His doctoral dissertation was the first large-scale study of structure-activity relationships for adenosine receptors. During a joint postdoc with John W Daly at NIH and Solomon Snyder at Johns Hopkins, he developed the first adenosine receptor binding assay. He then joined WL/PD, where his lab demonstrated the existence of two subtypes of the adenosine A2 receptor, A2a and A2b. In 1988, he joined Lilly as a receptor biologist in charge of a high-throughput screening lab. He taught himself chemoinformatics as a way to optimize compound selection for screening, and in 1997 switched to computational chemistry full-time. He supported the D1 PAM project in various roles from its inception in 2002 until selection of a clinical candidate in 2013. Dr. Bruns has over 80 publications and 11,000 citations, with an h-index of 47. Dr. Robert F. Bruns on the web ResearchGate LinkedIn Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>