<< Back to podcast list Strategic Partner(s) Dr. Davide Calebiro About Dr. Davide Calebiro "Davide Calebiro is Chair of Molecular Endocrinology and Wellcome Trust Senior Research Fellow at the Institute of Metabolism and Systems Research (IMSR) of the University of Birmingham and Co-Director of the Centre of Membrane Proteins and Receptors (COMPARE) of the Universities of Birmingham and Nottingham. He studied Medicine in Milan and Stockholm, and obtained a PhD in Molecular Medicine and a Clinical Specialisation in Endocrinology and Metabolic Disease from the University of Milan. Between 2009 and 2017, he was a Group Leader at the Institute of Pharmacology and Toxicology and Rudolf Virchow Center of the University of Würzburg, Germany. He leads a multidisciplinary research team comprising biologists, chemists, physicists, engineers and computer scientists focusing on the basic mechanisms of G protein-coupled receptor (GPCR) signalling and their alterations in endocrine, metabolic and cardiovascular diseases. To study GPCR signalling, they develop and use innovative optical methods based on FRET and single-molecule microscopy, which allow them to directly observe signalling events in living cells and tissues with unprecedented spatiotemporal resolution. His major scientific contributions include the discovery that GPCRs are not only active at the plasma membrane but also at intracellular sites and that these receptors interact among themselves and with other membrane proteins to form dynamic nanodomains at the plasma membrane. Davide’s work has been published in prestigious scientific journals such as Nature, Cell, New England Journal of Medicine, Journal of Clinical Investigation, PLoS Biology, PNAS, Nature Communications and Science Advances, attracting several prizes and awards. He has served on multiple panels and committees, including the ENDO Annual Meeting Steering Committee and the MRC Molecular & Cellular Medicine Board." Dr. Davide Calebiro on the web University of Birmingham Twitter 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) 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 >>

Livingston on allosteric opioid modulators, receptor internalization, and navigating the transition from academic GPCR research to biotech. << Back to podcast list Strategic Partner(s) Kathryn Livingston: Allosteric Opioid Modulators and Receptor Signaling Beyond the Membrane Opioid receptors belong to a class of GPCRs where the pharmacology extends well beyond what equilibrium binding data can show. The first allosteric modulators of opioid receptors were discovered through an academic-industry collaboration and immediately raised a foundational question: without competing for the orthosteric site, how do these compounds actually work? Livingston's PhD research at the University of Michigan addressed this systematically - mapping selectivity, mechanism, and the long-term consequences of modulator exposure on receptor desensitization and tolerance acquisition. Her postdoc in von Zastrow's lab at UCSF introduced a different framework entirely. Rather than measuring endpoint states, she learned to watch receptors move, internalize, and continue signaling from inside the cell - a finding that challenged the membrane-centric assumption underlying much of classical receptor pharmacology. The conversation traces the scientific and personal logic behind each transition: from chemistry to pharmacology, from membrane to endosome, from bench to product development. For Livingston, GPCRs were never purely academic - her entry into the field began with a forensic toxicologist father who tested crime scene samples for controlled substances, and a question about why molecules change who we are. About the Guest Livingston completed her PhD in pharmacology at the University of Michigan, where she investigated the first allosteric modulators of opioid receptors under Traynor, characterizing their selectivity, binding mechanisms, and effects on acute and chronic receptor signaling. She trained as a postdoctoral fellow in von Zastrow's lab at UCSF, where she worked on beta-2 adrenergic receptor internalization using live-cell imaging approaches that track receptor dynamics in real time. She now works at Gator Bio, where she transitioned from Field Application Scientist - serving as a technical liaison between GPCR researchers and analytical instrumentation - to Product Manager, translating customer research needs into commercial tools. Scientific Themes of the Conversation Allosteric modulation of opioid receptors - mechanism, selectivity, and therapeutic rationale Receptor internalization and post-endocytic signaling as a paradigm shift in GPCR pharmacology Assay design as an epistemic constraint on pharmacological interpretation Equilibrium vs. dynamic frameworks for studying receptor biology The Field Application Scientist as a career model for GPCR-trained scientists The structural complementarity of academic and industry research in drug discovery Key Insights from the Conversation 1. Allosteric opioid modulators bypass the orthosteric site entirely Rather than competing with morphine or endogenous opioids at the binding pocket, allosteric modulators act at a distinct site on the receptor. Livingston's PhD project was among the first to characterize how these compounds operate - mapping whether activity is receptor-dependent, whether they shift affinity or efficacy, and whether effects persist through desensitization and tolerance. The therapeutic logic is that decoupling from the orthosteric site might preserve pain relief while altering the signaling profiles responsible for side effects. 2. Internalized receptors don't stop working The membrane-centric view of receptor pharmacology assumes signaling ends when a receptor is endocytosed. Von Zastrow's lab challenged this directly, demonstrating that GPCRs continue to generate signals after they leave the cell surface. For Livingston, encountering this finding after a PhD grounded in equilibrium binding required a genuine conceptual reset - the receptor she had been mapping was not anchored to the membrane in the way her training had assumed. 3. An assay measures a specific thing - not the biology you assume it measures One of Livingston's most consistently held principles: understanding exactly what your assay is measuring is not optional. A readout that captures a downstream marker, a surrogate signal, or a population average can yield clean data while systematically pointing in the wrong direction. Misinterpreting assay specificity is, in her view, one of the most consequential and underacknowledged sources of error in pharmacological research. 4. Live-cell imaging makes the dynamic pharmacology of GPCRs visible Where equilibrium assays capture endpoint states, live-cell microscopy reveals what happens between them. During her postdoc, Livingston transitioned from pulling numbers off instruments to watching receptors traffic, cluster, and internalize in real time. She describes the shift as both technically disorienting and visually striking - a different relationship to data than any endpoint assay can produce. 5. Academia and industry are structurally complementary - not competing versions of the same thing Academia can sustain a 15-year investigation of a single receptor question. Industry can screen tens of millions of compounds in the time it takes to write a grant. Livingston argues these structural constraints make the two sectors dependent on each other - and notes that her PhD emerged directly from an academic-industry collaboration that would not have produced the allosteric modulators without both sides present. 6. The Field Application Scientist role is one of the least-known best fits for GPCR-trained scientists The FAS role combines technical depth, customer-facing science, and teaching - a combination Livingston describes as a natural extension of what she valued most in training. The role is rarely discussed in academic career advising, yet it draws directly on GPCR pharmacology skills: deep assay knowledge, the ability to troubleshoot complex data, and fluency across multiple experimental systems. Episode Timeline Timestamps are AI-generated based on transcript analysis and may not reflect exact chapter breaks in the final audio or video. Use as a navigational guide. 00:00 Introduction and ecosystem announcements 02:15 From inorganic chemistry to GPCR pharmacology 03:17 The origin story - forensic toxicology, mental disorders, and GPCRs 06:58 PhD research: first allosteric modulators of opioid receptors 11:58 Know your assay - and why getting it wrong costs more than data 12:36 Choosing von Zastrow's lab and the internalization paradigm shift 14:17 How to choose a postdoc with no trial period 19:07 Beta-2 adrenergic receptors and live-cell imaging at UCSF 22:02 The moment academia stopped making sense 30:54 From Field Application Scientist to Product Manager 38:58 What both roles look like day-to-day 39:28 Three steps for PhDs and postdocs considering industry Selected Quotes "Instead of directly targeting the receptor like morphine or buprenorphine, we target allosterically. We enhance your endogenous tone, we cause pain relief, maybe we mitigate some of these side effects." "To go to Mark's lab where everything is dynamic, everything is moving - this is a live cell where pieces are internalizing, moving - and then to flip it on its head again and say the receptor at the surface might not be the center of the world." "You have to know what your assay is actually measuring. Because you can get this data and you interpret it one way, but if you don't know the nuances, the very intricacies about your assay - you don't actually know what the specificity of the thing you're measuring is - then you can interpret it in a really wrong way." "In industry, you can't spend 15 years trying to solve one problem. There's no way. But in academia, you also can't screen 30 million cell lines in an afternoon. They're completely complementary." About Dr. Kathryn E Livingston Dr. Kathryn E Livingston is currently a Product Manager at Gator Bio , a biotechnology company providing solutions to researchers studying protein-protein interactions. Kathryn obtained her BS in Chemistry from Carnegie Mellon University and went on to receive a Ph.D. in Pharmacology at the University of Michigan. Working under the supervision of Dr. John Traynor , Kathryn worked to develop and understand first-in-class allosteric modulators of opioid receptors. Research into their mechanism of action in purified systems formed the base of her thesis work. Following this, Kathryn did a post-doctoral fellowship at UCSF in the laboratory of Dr. Mark von Zastrow . There she researched the beta-2 adrenergic receptor and developed assays to investigate real-time activity in intact cellular systems. Kathryn’s passion is developing solutions to problems in whatever form is most efficient: novel instrumentation, novel methods, or novel communication. Dr. Kathryn E Livingston on the web LinkedIn 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) The Scientist's Compass: From Academia to Entrepreneurship with Dr. Dmitry Veprintsev In this episode, Yamina sits down with Prof. Dmitry Veprintsev , a molecular pharmacologist at the University of Nottingham, to discuss his scientific journey, GPCR research, and the intersection of academia and entrepreneurship. Key Takeaways: From Protein Folding to GPCRs – How Dmitry transitioned from biophysics and protein folding to cannabinoid receptor research, guided by key mentors like Michel Bouvier. Why GPCRs? – The challenge and excitement of working with notoriously difficult-to-study membrane proteins. The Power of Asking the Right Question – Dmitry emphasizes that mastering a technique isn’t enough—true scientific breakthroughs come from formulating the right biological questions. Building Z7 Biotech – The unexpected journey into biotech entrepreneurship, providing GPCR profiling services to pharma and biotech companies. Interdisciplinary Research & Future Directions – Exploring combinatorial drug actions, receptor interactions, and novel profiling approaches. Networking & Career Growth – Overcoming introversion, the importance of talking to people, and how networking (or just genuine curiosity) opens doors in science. 💡 Big Takeaway? Whether in academia or industry, success comes from curiosity, persistence, and knowing your values. Tune in to hear how Dmitry navigated his career, the challenges of studying GPCRs, and why talking to others will always lead to answers! Summary made with AI About Dmitry Veprintsev Dmitry is Professor of Molecular and Cellular Pharmacology at the Centre of Membrane Proteins and Receptors (COMPARE), University of Nottingham, where he provides leadership in structural and biophysical pharmacology of G protein coupled receptors. He is author of over 100 papers, including several in Nature, Science and Cell. Dmitry studied biophysics at the Moscow State University, followed by a PhD (1998) in protein folding at the Russian Academy of Sciences and at the Ohio State University, USA. He joined the MRC Centre for Protein Engineering and later at the MRC Laboratory of Molecular Biology in Cambridge, UK as a postdoctoral fellow and later as a staff scientist, focusing on the biophysical studies of the tumour suppressor p53. In 2010 he became a group leader at the Paul Scherrer Institute and ETH Zürich in Switzerland, changing his attention to structural pharmacology of G protein-coupled receptors (GPCRs). In 2017 Dmitry became a full professor at the Centre of Membrane Proteins and Receptors, COMPARE, a joined venture between the University of Birmingham and the University of Nottingham. In 2021 he co-founded Z7 Biotech, developing and providing innovative GPCR drug screening and precision pharmacology services. Dmitry Veprintsev on the web LinkedIn Veprintsev Lab Z7 Biotech University of Nottingham 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 >>

Randy Hall on the receptor tail the field ignored, the adhesion GPCR experiment that did the opposite of what he expected, and writing Lefkowitz's memoir. << Back to podcast list Strategic Partner(s) Randy Hall: Adhesion GPCRs and the Tail Nobody Wanted SCIENTIFIC ABSTRACT Most of what the field now takes for granted about the C terminus of a GPCR was, in the mid 1990s, considered uninteresting. Randy Hall arrived in Bob Lefkowitz's lab from a background in ionotropic glutamate receptors, noticed that the beta adrenergic receptors carried short motifs resembling the ones that recruit scaffold proteins to NMDA receptors, and asked what bound there. He was told the answer was nothing. At the time, the lab chasing the first GPCR crystal structure was cutting the tail off entirely. What he found reframed how the field explains why closely related receptor subtypes produce different effects on cell physiology. This conversation follows that thread into adhesion GPCRs, a subfamily of 33 human receptors with enormous extracellular N termini that cleave themselves and then stay together. Hall describes the experiment designed to kill receptor signaling that instead amplified it, the tethered agonist model his lab proposed in 2011, and why a family once dismissed as undruggable now looks like a serious therapeutic frontier. He also explains how he came to write the memoir of his mentor, a project he pitched three times over fifteen years before the answer was yes. ABOUT RANDY Randy Hall is Professor of Pharmacology and Chemical Biology at Emory University School of Medicine, where he has run his lab since 1999. He trained with Gary Lynch at UC Irvine on ionotropic glutamate receptors, then with Thomas Soderling at the Vollum Institute on receptor trafficking and phosphorylation, before joining Bob Lefkowitz's lab at Duke to work on adrenergic receptor regulation. His lab uses proteomic and interaction screening approaches to map the proteins that bind GPCR intracellular tails, and has published on receptors from the adrenergic, purinergic, glutamatergic, GABAergic and adhesion subfamilies. Recent work centers on GPR37 and GPR37L1 and on the adhesion receptors BAI1, BAI2 and GPR56, with a particular focus on disease associated mutations that disturb receptor signaling or trafficking. He is a Fellow of the AAAS and coauthor, with Bob Lefkowitz, of the 2021 memoir A Funny Thing Happened on the Way to Stockholm. SCIENTIFIC THEMES OF THE CONVERSATION - Why the GPCR C terminus turned out to determine subtype specific function - Adhesion GPCRs: self cleaving receptors, huge N termini, and the tethered agonist model - Constitutive activity as a disease mechanism, from the alpha 1 receptor to BAI2 - Orphan receptors and where the next generation of GPCR drugs will come from - In silico screening, and what human plus machine collaboration means for drug discovery - Problem selection: how young scientists choose what to spend years on - Writing a scientific memoir, and why honesty is the load bearing part KEY INSIGHTS FROM THE CONVERSATION Changing subfields is when discovery happens Hall deliberately chose a second postdoc in a different receptor family rather than extending his graduate work. He argues that staying close to a hot topic feels safe but narrows a scientist's development, and that the moment you carry one field's questions into another is often the most productive window of a career. His own case is the evidence: NMDA receptor scaffolding logic applied to beta adrenergic receptors. The tail everyone was discarding When Hall asked what the C termini of the beta adrenergic receptors did, the lab's answer was that they could be removed with G protein coupling intact. The structural effort underway at the time simply deleted them. That consensus is precisely why he went looking, and the distinct binding partners he found for beta 1 and beta 2 offered an explanation for how two subtypes coupling to the same G protein can have opposite effects on cell physiology. Skepticism first, then a crowded field The early data drew hard questions at Gordon conferences from senior figures who were not convinced. Within a few years, dozens of labs were running similar studies across every GPCR subfamily. Hall describes the real measure of acceptance as the moment other groups start doing the experiments themselves. The experiment that did the opposite Predicting that an endogenous ligand acted on the large N terminus of GPR56, his lab truncated it, expecting a dead receptor. Signaling increased massively instead, and the same held for BAI1. That inversion became the basis for the model his lab proposed in 2011, in which removing or reconfiguring the N terminus unveils a cryptic tethered agonist, and it has since been reproduced across the family by other groups. From undruggable to promising Drug development veterans long treated large adhesive proteins as poor targets because their interaction interfaces are too big to disrupt with small molecules. Hall's counterpoint is that adhesion GPCRs are not only adhesive proteins, they are also GPCRs, with a seven transmembrane pocket. Screening work has since produced agonists and antagonists, and the first cryo EM structure of an adhesion GPCR, GPR97, showed glucocorticoid binding, raising the possibility that steroid activation of G protein pathways has been hiding in this family. When receptors are tuned and mutations detune them The BAI2 mutation Hall's lab linked to a neurodegenerative condition sits on the C terminus and makes the receptor constitutively overactive, pointing back to the protein interactions he has studied since the 1990s. He traces the concept to basic work by Susanna Cotecchia on the alpha 1 receptor in the early 1990s, research with no clinical intent that became the template for explaining a long list of human diseases. Choose important problems, not easy ones Hall's advice to junior scientists is that trivial questions are not measurably easier to solve than important ones, so the years spent are better invested in something that matters. He recommends heading for subfields in turmoil, where there is disagreement and unsolved mystery, with the single constraint that the technology to answer the question must already exist. EPISODE TIMELINE Timestamps were generated using AI for readability. - 00:00 Opening announcements - 01:34 Introducing Randy Hall - 02:02 The Feynman book, and pitching a memoir to Bob Lefkowitz three times - 06:45 Deciding which stories survive, and finding a publisher who believed in science memoirs - 17:03 Nature walks, synaptic plasticity, and falling for the first event in cell signaling - 19:39 Switching subfields, and spotting a motif nobody was looking at - 23:51 Pushback at Gordon conferences, and what acceptance actually looks like - 26:34 Moving the lab toward orphan and adhesion GPCRs - 34:00 The truncation that was supposed to kill signaling - 37:34 Pulling the pin from the grenade: the tethered agonist model - 39:38 Are adhesion GPCRs druggable, and what GPR97 changed - 46:46 In silico screening, chess, and humans working alongside machines - 52:09 Disease mutations across the adhesion family - 1:00:41 Choosing important problems over easy ones - 1:07:10 Openings in the Hall lab SELECTED QUOTES "That was how lowly regarded the C terminus was. They were just throwing it in the trash." "Go for subfields where the seas are rough and the sky is dark and there are a lot of mysteries." "If you are surprised by the result of your own experiment, then probably other scientists will also be surprised." "There is no connection between the importance of a problem and how easy it is to solve." GUEST LINKS - Hall Lab: http://www.pharm.emory.edu/hall/index.html - LinkedIn: https://www.linkedin.com/in/randy-hall-79923839 - Google Scholar: https://scholar.google.com/citations?user=tfsXwHUAAAAJ&hl=en&oi=ao - ResearchGate: https://www.researchgate.net/profile/Randy-Hall - A Funny Thing Happened on the Way to Stockholm: https://www.simonandschuster.com/books/A-Funny-Thing-Happened-on-the-Way-to-Stockholm/Robert-J-Lefkowitz/9781643136387 - Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/search?q=Randy+Hall 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. Fiona Marshall on structure-based GPCR drug discovery, the GABA-B heterodimer, the acetate that rewrote a receptor family, and why the same names keep filling GPCR conference agendas. << Back to podcast list Strategic Partner(s) Fiona Marshall: Three Decades Inside GPCR Drug Discovery This conversation traces how structure-based GPCR drug discovery moved from a stubborn crystallography problem to a generative platform — through the career of a scientist who helped engineer that shift. Dr. Fiona Marshall walks through the decade when membrane proteins kept failing to crystallize in detergent, and how Chris Tate's thermostabilization strategy finally made GPCR structures routine, the insight that seeded Heptares Therapeutics. The conversation moves across discoveries that shaped a generation of GPCR pharmacology: the GABA-B heterodimer, the free fatty acid receptors, the unexpected allosteric pockets that emerged once structures became available. It also confronts where the field still struggles — translating biased agonism from cell line to clinic, drugging orphan receptors without obvious phenotypes, and expanding the voices that define the field's agenda. For Dr. Marshall, the throughline is personal: she remembers the exact lecture at Bath where she first heard about the β-adrenergic receptor, and has spent three decades inside the rooms where GPCR drug discovery actually changed. About the Guest Dr. Fiona Marshall is VP and Head of Neuroscience Discovery at MSD, leading teams in West Point, Boston, and London. She co-founded Heptares Therapeutics and served as Chief Scientific Officer for twelve years, through the company's acquisition by Sosei, helping establish structure-based drug design as a productive strategy across GPCR families. Earlier, at GSK, she contributed to the identification of RAMP proteins, the GABA-B heterodimer, and ligands for orphan receptors including what are now known as FFA2 and FFA3. Her work spans GPCR structural biology, membrane protein stabilization, allosteric modulation, and the pharmacology of receptor families implicated in neuroscience, immunology, and metabolism. Scientific Themes of the Conversation Structure-based GPCR drug design and the thermostabilization breakthrough GPCR heterodimerization and the logic of accessory proteins (RAMPs, GABA-B1/B2) Allosteric modulation and non-orthosteric binding sites on GPCRs Biased agonism, target validation, and animal-to-human translation failure Orphan GPCRs and the missing pharmacology of ~100 unassigned receptors GPCRs in oncology, immunology, and microbiome-host signaling Key Insights from the Conversation Why Membrane Proteins Wouldn't Crystallize The bottleneck wasn't expression level, as most groups had assumed — it was the instability of the receptor in detergent. Chris Tate's thermostabilization strategy, which introduced stabilizing mutations selected by thermal assay, reframed the problem and opened the door to routine GPCR crystallography. Dr. Marshall is clear that the conceptual reframing, not a brute-force technical push, is what unlocked the field. The GABA-B Heterodimer Was Hiding in Plain Sight Dr. Marshall's team at GSK cloned GABA-B1, tried to get it to signal, and couldn't. A screen run to find an intracellular scaffolding partner pulled up something unexpected: a second GABA-B receptor. The moment baclofen activated ion channels in Xenopus oocytes expressing both — with Dr. Marshall in the room — a new category of GPCR biology opened, with heterodimers as obligate signaling units. The Ligand That Wasn't the Ligand Screening orphan receptors in yeast, the team chased peptide hits that made no SAR sense. The realization — triggered by Andrew Brown sitting with a table of actives and inactives — was that the active condition was the acetate buffer, not the peptide. The orphan was a free fatty acid receptor. Years of assumed peptide biology dissolved into a simpler truth hidden in the solvent. Structures Reveal Pockets the Field Didn't Know Existed Once GPCR structures became routine, unexpected binding sites emerged: extra-helical pockets on the glucagon receptor, intracellular sites for C5a antagonists, allosteric modulators bound far outside canonical regions. These discoveries rewrote what counts as "druggable" on receptors once considered fully mapped. Biased Agonism Needs Human Biology, Not Just Pathway Dials The promise of biased ligands — pulling one signaling arm while sparing another — only survives translation if the coupling profile in the relevant human cells matches the cell-line model. Dr. Marshall's caution is hard-won: many animal-model-validated GPCR drugs have failed in the clinic precisely because this step was skipped. Oncology Ignored GPCRs for Decades — and Is Paying Attention Now Twenty years ago, cancer biologists dismissed GPCRs: they weren't oncogenic and didn't kill tumor cells directly. The shift came through the tumor microenvironment — immune cells, chemokine receptors, adenosine signaling — where GPCRs now sit at the center of immuno-oncology strategies that tumor-intrinsic target lists missed. Thirty Years, and the Same Names Keep the Mic One of Dr. Marshall's most pointed observations: the people speaking at GPCR conferences today are, in large part, the people who were speaking at them twenty-five years ago. She frames this as a scientific problem — a narrowing of perspectives on hard problems — not only a social one, and argues the old guard should actively make room for the next cohort. Episode Timeline Timestamps were generated using AI for readability. 00:00 Welcome and guest introduction 02:32 How an undergraduate lecture on β-adrenergic signaling set a career in motion 07:07 A venture capital visit to the LMB and the founding of Heptares 11:28 Building a membrane protein team from scratch 15:29 Unexpected allosteric pockets and the next wave of GPCR drug design 18:47 Which GPCR families pharma is chasing now — and why 21:23 Why animal model validation keeps breaking in clinical trials 27:33 How oncology finally stopped ignoring GPCRs 36:39 The GABA-B heterodimer — the moment baclofen finally worked 40:06 The acetate-in-the-buffer discovery 41:47 Thirty years in, and the same speakers keep getting the mic Selected Quotes "We did the classic experiment in Xenopus oocytes, where you inject the cDNA of both the receptors together. And I was in the room when we then added on baclofen, the agonist, and we could see the ion channel activation." "He just sat down with a table of what was active or inactive. And then he realized the peptides that had been dissolved in acetic acid or acetate were the ones that were active... So it turned out that the ligands were not the peptides at all." "Having worked in GPCRs for 30 years and I look at the conferences, the same people are speaking now as was speaking 25 years ago. So can we now try and encourage the next cohort of people to be the main speakers at conferences?" "We had this really cool room where you could see — you put on 3D glasses and see the receptor in three dimensions sort of floating in the room and moving around." About this episode Fiona Marshall got fascinated with GPCRs after attending a lecture on how the beta-adrenergic receptor in the heart is activated by adrenaline, during her undergraduate studies at Bath University. She then pursued her Ph.D. in neuroscience at Cambridge University. An expert in GPCR biology, Fiona published the first description of the cloning and structural requirements of the GABAB receptor. One of her career path-defining moments came when she visited Dr. Chris Tate and Dr. Richard Henderson at the Laboratory of Molecular Biology in Cambridge, UK. As a co-founder of Heptares Therapeutics , now called Sosei Heptares , a GPCR-focused drug discovery and development biotechnology company, Fiona and her team made considerable breakthroughs in the field of GPCR stabilization and structure-based drug design. Today, Dr. Marshall is the VP Head of Neuroscience Discovery and Head of Discovery UK, Global Head of Neuroscience discovery research leading teams in West Point, Boston, and London at MSD. Join me and learn more about her fascinating career trajectory. Dr. Fiona Marshall on the web LinkedIn Twitter Google Scholar MSD UK 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. Nicola J. Smith About Dr. Nicola J. Smith Dr. Nicola J Smith is an expert in molecular pharmacology with a track record in exploring GPCR structure-function relationships in the context of cardiovascular disease and metabolic disorders. She is a National Heart Foundation of Australia Future Leader Fellow and runs a laboratory of 7 Ph.D. and Honours students at UNSW Sydney, where she has recently been promoted to Associate Professor. Most recently, Dr. Smith’s team has made advances in the understanding of how an orphan GPCR exerts its effects both in vitro (cell culture and ex vivo models) and in vivo (measures of physiological and pathological cardiometabolic function in unconscious and conscious mice). Together with Irina Kufareva , UCSD, her team developed a novel approach to identifying ligands for orphan GPCRs by developing a powerful new computational tool for identifying ‘surrogate’ ligands (borrowed from other receptors) for orphan GPCRs, named GPCR-CoINPocket. Her career goal is to leverage this expertise to establish a research program that takes orphan GPCRs from ‘locked’, inaccessible receptors to well-characterized and understood ‘unlocked’ therapeutic targets with high-affinity ligands. Dr. Nicola J. Smith on the web UNSW Sydney LinkedIn Retraction Watch 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. 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. Hannes Schihada About Dr. Hannes Schihada Following studies in Pharmacy in Regensburg, Germany, I joined the receptor pharmacology group of Martin Lohse at the Institute of Pharmacology & Toxicology in Würzburg, Germany, in 2015. My project involved the development of FRET/BRET -based GPCR conformational biosensors, which can be employed in high throughput ligand screening. After my Ph.D. defense in 2019, I moved with a DFG (German research council) PostDoc fellowship to Stockholm, Sweden, in order to focus my research on class Frizzled GPCR s in the lab of Gunnar Schulte at the Karolinska Institute. I spent 2 1/2 years in his lab and developed novel conformational sensors for these intriguing receptors, allowing us to better understand their mode of action. By the end of 2021, I moved back to Germany and joined the pharmaceutical chemistry group of Peter Kolb in Marburg. I was recently awarded a Marie Sklodowska Curie PostDoc Fellowship in order to investigate and find better ligands for the orphan class A GPCRs , GPR3 , GPR6 , and GPR12 . Dr. Hannes Schihada on the web Karolinska Institutet Twitter Adher´n Rise 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. Maria Waldhoer on why endpoint GPCR assays miss most of what ligands do — and what kinetic pharmacological fingerprints reveal instead. << Back to podcast list Strategic Partner(s) Maria Waldhoer: Pharmacological Fingerprints and the Limits of Bias Dr. Maria Waldhoer, CSO of InterAx Biotech AG, argues that endpoint assays — the field's default way of characterizing GPCR ligands — throw away most of the information a compound actually carries. Her team at InterAx models receptor signaling pathways as systems of time-dependent equations, then runs kinetic assays to refine the models and extract ten to fifteen pharmacological parameters from what would otherwise be three endpoint numbers. The approach sits in deliberate tension with the prevailing vocabulary of bias factors and functional selectivity, and with the common dismissal of HEK293-based work as too artificial to matter. Her answer to that dismissal is partly methodological and partly personal: the proudest moment of her scientific life was designing a compound in a HEK cell from a hypothesis, putting it in an animal, and watching the effect come back exactly as predicted. The conversation traces her path from neurobiology in Salzburg through academic labs in Vienna, Copenhagen, and Graz, to six and a half years at Novo Nordisk, and into biotech at InterAx — where the next challenge is using functional fingerprints to design ligands, not just describe them. About the Guest Dr. Maria Waldhoer is Chief Scientific Officer at InterAx Biotech AG in Switzerland. Her training began in zoology and neurobiology in Salzburg, followed by a PhD on GPCRs in Michael Freissmuth's lab in Vienna and postdoctoral work with Thue Schwartz in Copenhagen and Jennifer Whistler in San Francisco. After running her own academic group in Graz, she spent six and a half years at Novo Nordisk in early drug discovery, focused on incretin receptors. She has been at InterAx since 2017, where she leads the development of a computational systems biology and AI platform that produces time-resolved pharmacological fingerprints of GPCR ligands. Scientific Themes of the Conversation Kinetic versus endpoint characterization of GPCR ligands Systems biology modeling of receptor signaling pathways Pharmacological fingerprints as multi-parameter compound descriptors Ligand residence time as a driver of drug action AI combined with functional, not only structural, data The academic-to-Big-Pharma-to-biotech trajectory Key Insights from the Conversation Endpoint assays collapse the ligand's signature. Standard assay kits that read cAMP at thirty minutes or arrestin recruitment at ten collapse time-resolved signaling into a single number. Dr. Waldhoer argues that most of what distinguishes one compound from another lives in the shape of the kinetics, not the endpoint value. Model first, pipette second. InterAx treats GPCR pharmacology the way engineers treat aircraft design: build the mathematical model of the signaling pathways first, then use controlled kinetic assays as the "wind tunnel" that refines the model. Inverting the usual order changes what the experiment can be asked to do. Three inputs can yield fifteen outputs. With a well-constructed computational model and a small set of kinetic assays, one compound on one receptor can be described by ten to fifteen pharmacological parameters — internalization rates, recycling and degradation rates, G protein affinity for the ligand-receptor complex, and more — rather than a single EC50 or a single bias number. The HEK293 cell earned its keep. Her most formative scientific moment was designing a compound in HEK293 cells from a hypothesis at Novo Nordisk, putting it in an animal, and watching the effect come back exactly as predicted. The "artificial system" critique misses what those systems do for people who know how to ask the right questions of them. Bias factor is a start, not an answer. Functional selectivity has been in the vocabulary since her PhD years in Vienna. Picking a single time point for a single pathway and computing a bias factor captures far less than looking at how several pathways evolve over time — especially for compounds with unusual kinetics. The next challenge is multi-receptor, multi-disease complexity. With comorbidities and aging populations driving drug discovery, the one-receptor-one-drug frame is increasingly inadequate. The computational tools that now describe single receptors will need to extend to how multiple receptors in the same cell, in a diseased tissue, at a particular age, interact. Young founders should not build alone. The hardest-won lesson of her biotech years: great science does not rescue a company from inexperienced management. Scientists starting companies need experienced operators around them, and the honesty to know when to bring them in — a theme she returns to as her farewell message. Episode Timeline Timestamps were generated using AI for readability. 00:00 — Opening: end-of-2020 wrap-up, January break, announcements 01:28 — Meet Dr. Maria Waldhoer, CSO of InterAx Biotech 02:19 — From zoology to GPCRs: fate, not choice 06:48 — Academia to Big Pharma: speed, scale, and decisions from above 09:58 — InterAx's pivot from arrestin biosensors to kinetic systems biology 14:31 — Why endpoint numbers miss what a ligand is really doing 16:40 — AI plus "real intelligence": functional data in drug design 21:48 — Comorbidities, aging, and the multi-receptor frontier 24:07 — "What endogenous level would you like me to mimic?" 25:26 — The HEK293 experiment that predicted the animal 31:21 — Tools for the next decade: biosensors, tissues, high-throughput structure 38:43 — Career advice for scientists eyeing industry or biotech 42:35 — On starting a GPCR company: why not too early 57:30 — Aha moments, including the EU grant pitch in Brussels 01:01:53 — "You're only as good as the other people you're with" Selected Quotes "A long way through the bright and the dark side of science." "What endogenous level would you like me to mimic?" "We combine AI with RI — with real intelligence." "You're only as good as the other people you're with." About this episode Dr. Maria Waldhoer is originally from Austria. She earned her M.Sc. in Zoology and Neurobiology before completing a Ph.D. in Biology and Pharmacology at the University of Vienna. GPCRs led Maria to Thue W. Schwartz’s lab in Copenhagen where she completed her postdoctoral training. After working in the US and at the University in Graz in Austria, Maria worked several years at Novo Nordisk before joining InterAx Biotech in Switzerland as their Chief Scientific Officer. Even though Maria stumbled upon the GPCR field, her 20 years in both academia and in the industry working on GPCRs make her a strong and dedicated scientific leader. Dr. Maria Waldhoer on the web LinkedIn InterAx Biotech 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. Gregory Tall About Dr. Gregory Tall " Dr. Gregory Tall earned his Ph.D. in Biomedical Sciences from U.T. Southwestern Medical Center with Bruce Horazdovsky, Ph.D. They worked on the interactome of yeast and mammalian Rab5 homologs including identification of Rab5 GEFs. In 2000, Dr. Tall moved upstairs to conduct his postdoctoral work on heterotrimeric G proteins and the novel interactor, Ric-8 with Alfred Gilman, M.D. Ph.D. In 2007, Dr. Tall joined the faculty in the Department of Pharmacology and Physiology at the University of Rochester Medical Center, there establishing his lab and major research directions. Dr. Tall moved to the University of Michigan in 2016 as an Associate Professor of Pharmacology and is a current active member of the department. The current goals of the Tall lab are to understand the basic mechanism by which Ric-8 proteins fold all heterotrimeric G protein alpha subunits, to exploit a Ric-8-based technology to purify recombinant G proteins and to use the G proteins in assays to explore the mechanisms of action of the 33-member adhesion GPCR family or Family B2 GPCRs. We found that adhesion GPCRs are activated by a tethered peptide agonist mechanism that differed from the common example known at the time, protease activated receptors (PARs). PARs have an N-terminal leader sequence that is clipped by exogenous proteases to reveal a new N-terminus that serves as the tethered agonist. Adhesion GPCRs pre-cleave themselves and the two resultant fragments of the receptor remain together to conceal the tethered peptide agonist. Mechanical dissociation of the two fragments aided by protein binding ligands and cell movement serves to decrypt the tethered agonist for binding to its orthosteric site. Our current goals are to explore this mechanism in detail and to understand how it may happen for the 33 adhesion GPCRs in complex physiological contexts…one being our discovery that GPR56 is the platelet receptor that senses collagen and shear force to initiate the platelet activation program. Dr. Tall has been continuously funded by the NIH since receiving an early RO1 award at Rochester. He has continued funding at Michigan through the MIRA R35 program. Dr. Tall has presented his work at 59 invited seminars including national and international meetings and academic departmental seminars. " Dr. Gregory Tall on the web The Tall Lab University of Michigan Google Scholar 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 >>

mGlu2 can suppress drug seeking across four addictive substances - but its clinical results have never been published. Johnson explains why the circuit matters more than the receptor. << Back to podcast list Strategic Partner(s) Kari Johnson: mGlu2, Addiction, and the Brain Circuits Alcohol Rewires The brain circuits governing reward, motivation, and decision making are not fixed - they are continuously reshaped by experience. In alcohol use disorder and other substance addictions, one of the most consequential changes is the shift from goal-directed to habitual behavior: a state in which drug seeking persists not because of pleasure, but because the underlying circuit no longer responds to consequences. mGlu2, a presynaptic metabotropic glutamate receptor coupled to Gi/o proteins, sits at a critical junction in this process. By suppressing glutamate release across circuits in the basal ganglia, mGlu2 is positioned to modulate drug seeking, habit formation, and reward processing - and has been pursued as a potential therapeutic target in addiction, depression, schizophrenia, and Parkinson's disease. Kari Johnson's research follows this receptor from the bench to the behaving animal, using optogenetics and circuit-selective mouse models to ask which specific corticostriatal pathways are driving behavioral change after alcohol exposure - and whether pharmacological rescue is possible after those circuits have already been disrupted. The question has been central to Johnson's career since long before the tools to answer it properly existed. ABOUT THE GUEST Kari Johnson is an assistant professor of neuropharmacology at the Uniformed Services University of Health Sciences in Bethesda. Her lab investigates how GPCRs modulate synaptic transmission in brain circuits involved in reinforcement learning, with a particular focus on how chronic alcohol exposure disrupts those mechanisms across levels ranging from gene expression to neural circuit function to behavior. She trained in high-throughput drug discovery at Vanderbilt - contributing to early functional assay development for metabotropic glutamate and muscarinic receptors - before completing postdoctoral training at the National Institute on Alcohol Abuse and Alcoholism with Dave Lovinger. Her current work combines whole-cell patch clamp electrophysiology, optogenetics, and operant behavioral pharmacology to study mGlu2 function in specific corticostriatal circuits and its role in the transition from controlled to compulsive drug use. SCIENTIFIC THEMES OF THE CONVERSATION mGlu2 as a convergence target across addiction, psychiatric disease, and movement disorders Circuit-specific GPCR modulation and the "modulomics" framework Goal-directed versus habitual behavior as a mechanistic framework for understanding addiction Pharmacological rescue of alcohol-disrupted receptor function using positive allosteric modulators The translational gap: why a decade of preclinical mGlu2 evidence has not yet reached clinical success The limits of brain slice electrophysiology - and why optogenetics redefines the questions the field can ask KEY INSIGHTS FROM THE CONVERSATION mGlu2 Sits at the Center of Multiple CNS Disorders Because mGlu2 regulates glutamate release in brain regions linked to reward, executive function, motivation, and stress responses, it has become a target of interest across an unusually broad disease landscape - alcohol use disorder, schizophrenia, depression, Parkinson's disease, and multiple other substance addictions. That breadth is a signal of the receptor's centrality in CNS function. It is also a complication: a receptor that modulates so many circuits will inevitably produce wanted and unwanted effects that are difficult to predict from any single experimental system. Alcohol Disrupts mGlu2 - But a PAM Can Restore It Johnson's lab demonstrated that adolescent alcohol exposure disrupts mGlu2 function in the striatum in a way that might seem to close off therapeutic targeting - if the receptor is impaired, can it still be activated pharmacologically? Their answer was yes: a positive allosteric modulator restored mGlu2 signaling even after alcohol-induced disruption. This finding shifts the question from whether mGlu2 is a viable target in addiction to how to reach it once its function has already been compromised. The Years Before the Tools Existed For most of the history of GPCR electrophysiology, researchers used electrical stimulation in brain slices and could observe that a receptor modulated synaptic transmission - but not which specific set of synaptic inputs was responsible. For Johnson, this was a formative constraint she navigated across her entire training: drawn to circuit-level questions that her early tools could not fully answer, she made the shift to optogenetics and genetically defined neuronal populations specifically because the biology demanded it. The tools arrived late relative to the questions. That gap, in Johnson's framing, is both a limitation of the past and an argument for the field's current momentum. Modulomics: Naming the Question Changes What You Can Ask Johnson's postdoc mentor Dave Lovinger coined the term "modulomics" to describe the systematic study of circuit-specific neuromodulation by GPCRs - using light-activated ion channels expressed in anatomically or genetically defined neurons to isolate receptor effects at individual synaptic inputs rather than across an entire stimulated pathway. Giving the approach a name formalizes it as a research program, not just a technique. Johnson's lab has extended this using conditional knockout mice that allow selective deletion of mGlu2 from specific cell types, enabling circuit-level pharmacology with direct behavioral readouts. The Habit Framework Changes What Addiction Means Pharmacologically The shift from goal-directed to habitual behavior is not just a behavioral description of addiction - it implies a specific circuit mechanism. Goal-directed behavior is sensitive to changes in outcome value; habitual behavior is not. When alcohol exposure biases the brain toward habit formation, the circuit underlying that inflexibility becomes the pharmacological target. Johnson's lab uses this framework to ask whether activating mGlu2 in specific corticostriatal circuits can reverse the habit bias that chronic alcohol produces - not just dampen the pleasure of drinking, but restore the flexibility of the decision that precedes it. Clinical Trial Results for mGlu2 Ligands Have Not Been Made Public Johnson noted that multiple clinical trials testing mGlu2 ligands in substance use disorders - including for smoking cessation and cocaine use disorder - have been conducted and completed. The results have not been released to the research community. Without access to those data, researchers cannot determine why promising preclinical findings did not translate, cannot adjust future trial designs, and cannot evaluate whether the receptor was genuinely ineffective or whether confounds such as prior antipsychotic exposure were responsible - a hypothesis already supported by subsequent preclinical work following the disappointing schizophrenia trials. The gap is consequential, and Johnson named it directly. Translating GPCR Research May Require Releasing Attachment to Specific Receptors One of Johnson's more quietly contrarian observations is that attachment to a "favorite receptor" may be limiting translational success. If mGlu2 activation produces the desired circuit effect in rodents but not in humans, the value of that work is not lost - it defines the functional target. A different receptor capable of achieving the same circuit-level effect in a human brain might carry the therapy further. The question, in Johnson's framing, is not which receptor you prefer, but which receptor is correctly positioned in the human circuit you need to modify. EPISODE TIMELINE Note: Timestamps are AI-generated from the transcript and may require manual verification after video editing. 00:00 Introduction 01:27 Johnson's career path - from Vanderbilt drug discovery to NIH postdoc to independent lab 07:31 Alcohol disrupts mGlu2 in adolescent mice - and a positive allosteric modulator rescues it 09:45 Why mGlu2 is Johnson's receptor of focus: synaptic plasticity and long-term depression 11:26 mGlu2 and drug seeking: preclinical evidence across alcohol, cocaine, methamphetamine, and heroin 13:28 How mGlu2 modulates dopamine release and the neurobiology of habit formation 16:28 Optogenetics and modulomics - studying circuit-specific GPCR function in the basal ganglia 20:45 Operant behavioral models: how habit formation is measured in mice 25:25 Clinical trials for mGlu2 ligands - what advanced, what disappointed, and what remains unpublished 28:41 Are GPCRs still good drug targets? A circuit-level argument 33:12 Advice for junior scientists: let the biology lead the method 35:28 Diversity in STEM and who carries the labor of change SELECTED QUOTES "Even if we see that these experiences cause an impairment in receptor function, there might be pharmacological strategies that we can use to rescue that." "We're really just beginning to scratch the surface of understanding how these receptors work in specific neural circuits - and that has the potential to impact our understanding of how they influence a really wide range of behaviors, especially since mGlu2 is expressed in so many different brain areas." "Maybe the effect that I want to have by activating mGlu2 has the effects I want in a rodent brain, but doesn't have it in a human brain. But maybe there's another receptor there that will have the effect that we want in the human brain." "Let the science lead you. If you take that approach, you'll have plenty of moments where you realize that a new tool could take your research to another level. But there's no reason to force it just because you feel like you should be incorporating a popular technique." About this episode Dr. Kari Johnson is currently an assistant professor at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. She is a neuropharmacologist with an interest in the long-term effects of alcohol abuse on neural circuits. Kari completed her Ph.D. in Pharmacology at Vanderbilt University before continuing her training as a postdoctoral fellow at the Vanderbilt Center for Neuroscience Drug Discovery, the National Institute of General Medical Sciences, and the National Institute on Alcohol Abuse and Alcoholism. All through her career, the recurring theme in Kari’s work has been GPCRs and more specifically Metabotropic Glutamate Receptors. Join me and learn more about how Kari studies GPCRs in basal ganglia circuits following chronic alcohol exposure in mice. Dr. Kari Johnson on the web LinkedIn Google Scholar Research Gate USU 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. 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 >>

A conversation with Dr. Silvio Gutkind on keeping a cancer research lab running at 10% occupancy, why rotation students act like a sorting hat, and why breakthroughs come from working hypotheses that fail. << Back to podcast list Strategic Partner(s) Silvio Gutkind: Building a Lab That Doesn't Shut Down Conversations that happen when a research community faces a shared constraint reveal as much about scientific practice as any experiment. Dr. Silvio Gutkind joins this resilience conversation from the UCSD Moores Cancer Center, where cancer patients cannot wait for normalcy to return. For Dr. Gutkind — carrying a personal loss in New York and leading a cancer center building that operated at 93% capacity during the early pandemic — the question was not abstract. He had to decide, week by week, what could pause and what couldn't, and whose careers would bear the cost of getting it wrong. He walks through the structure his team built: staggered schedules at 10–15% occupancy, written contracts with every lab member, a Zoom-based communication cadence, and an internal directive to read, think, plan, and write. The constraint did not slow the science; it redirected it. Bioinformatics projects flourished. Collaborations that would have waited for conferences started immediately. A harder question surfaces underneath: how much of what we call a lab is its physical walls, and how much is the community, the plan, and the willingness to let a failed hypothesis open a new direction? About the Guest Dr. Silvio Gutkind is Professor and Associate Director for Basic Science at the UCSD Moores Cancer Center. His research spans GPCR signaling in cancer biology, head and neck squamous cell carcinoma, and the molecular circuitry that drives tumor progression. Before moving to La Jolla, he spent decades at the NIH, where he led a branch at NIDCR. That dual lineage — extramural academic and intramural NIH — shapes how he thinks about research infrastructure, student training, and scientific community. Scientific Themes of the Conversation Institutional resilience and the architecture of a research lab under constraint The contract between scientific leadership and trainees during crisis Communication infrastructure as a substitute for physical proximity Chance and opportunity as drivers of a scientific career Rotation students as cross-pollinators between labs Why breakthroughs tend to come from working hypotheses that fail Key Insights from the Conversation Cancer centers don't get to pause. Dr. Gutkind describes operating his cancer research building at 93–94% capacity during the early pandemic because cancer patients couldn't wait for normalcy. The question was never whether to stay open — it was how to stay open safely, and how to absorb the stress that came with that responsibility. The NIH shutdown playbook made UCSD ready. Years at the NIH, where federal shutdowns were routine, gave Dr. Gutkind a pre-built mental model for what to freeze, what to protect, and what to let continue. When the pandemic hit, he reached for an infrastructure he already had. Every lab member needed a contract. Rather than making ad hoc decisions about who would come in and when, the team wrote down expectations — hours, distancing, critical versus deferrable work, and an explicit clause that no one should feel pressured to be on-site. The contract wasn't bureaucracy; it was protection, especially for students. The bioinformatics arm called it "heaven." Computational scientists suddenly had uninterrupted time at home with full data access and far fewer meetings. Dr. Gutkind reports that five years' worth of ideas accumulated in that stretch — more than the lab can realistically work through. "Physical distancing," not "social distancing." A small language correction with structural weight. Dr. Gutkind argues the scientific community grew closer during the pandemic, not further apart — the physical space contracted, but the community expanded through Zoom, shared drives, and unhurried collaboration conversations. Rotation students function like the sorting hat. Because trainees rotate through multiple labs, they carry science from one bench to another. Dr. Gutkind credits several of his most valuable collaborations to a rotation student recognizing a fit that no PI would have spotted from across campus. Breakthroughs come from working hypotheses that fail. Dr. Gutkind reflects that the most significant advances in his career didn't come from confirming a premise — they came from digging into why the premise broke. The discipline is not in being right, but in being willing to let go of the framework you built when the data refuses to fit it. Episode Timeline Timestamps were generated using AI for readability. 00:00 Welcome and introduction 01:46 Navigating research during the pandemic 03:30 Why cancer research couldn't stop 04:30 The NIH shutdown playbook 05:20 Writing the contract: occupancy, staggering, communication 06:50 The productivity paradox — "it's like heaven" 07:55 What will change after the pandemic 09:20 "Physical distancing, not social distancing" 11:31 Chance versus scientific knowledge in a career 12:20 Rotation students as the sorting hat 13:20 When the working hypothesis fails 14:30 Closing Selected Quotes "We have many more ideas than we can handle for at least the next five years." "I wouldn't call it social distancing — I would call physical distancing… as a community, we are even stronger." "These rotation students are like cross-pollination… almost like the sorting hat in Harry Potter." "Quite often, our breakthroughs are more often from when the working hypothesis did not work. The breakthrough came from getting deeper into why." About this episode Dr. J. Silvio Gutkind sheds light on his work and life since the beginning of COVID restrictions. A large component of his work is centered around dysregulated signaling in cancer and the development of novel mechanism-based cancer therapies. In this episode, Dr. J. Silvio Gutkind highlights how his past experience proves useful in current COVID times and potential benefits the changes in work environments can do for future collaborations. Dr. J. Silvio Gutkind on the web Gutkind Lab – UC San Diego Moores Cancer Center Gutkind Lab publications More Publications from the Gutkind Lab on Pubmed Dr. J Silvio Gutkind on LinkedIn 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 >>

Five scientists audit what AI can and can't do for GPCR drug discovery — from orphan receptors and biased signaling to the true-negatives problem nobody writes into grant proposals. Recorded at the 3rd EARNEST meeting. << Back to podcast list Strategic Partner(s) EARNEST Panel: Can AI Accelerate GPCR Drug Discovery? In October 2020, five scientists gathered virtually at the 3rd EARNEST meeting to debate a question that has only grown more urgent: can artificial intelligence actually accelerate GPCR drug discovery, or is it mostly a rebranding of methods the field has used for decades? Panelists from InterAx Biotech, Rockefeller University, and the University of New Mexico — computational chemists, systems biologists, structural biologists, and drug-discovery veterans — drew on their combined experience to separate what machine learning can credibly do for GPCR research from what still depends on pharmacological judgment. The conversation moves from definitional clarity (AI is not machine learning, and neither is simple computational modeling) to the practical realities of building usable datasets, deorphanizing receptors, handling generative models, and confronting the true-negatives problem that quietly breaks so many published models. For any scientist whose grant proposal now contains the phrase "machine learning" whether they fully believe in it or not, this panel is an honest audit of what the technology can deliver today and where it still falls short. About the Panelists Dr. Maria Waldhoer is Chief Scientific Officer at InterAx Biotech in Switzerland. A pharmacologist by training, she spent more than six years in early R&D at Novo Nordisk before turning to systems biology approaches for connecting in vitro signaling data to in vivo drug behavior. Dr. Aurélien Rizk is Chief Technology Officer at InterAx Biotech. Trained as a mathematician and computer scientist, his doctoral work focused on developing new methods for modeling GPCR signaling pathways. Dr. Yaroslav Nikolaev is a scientist at InterAx Biotech with a dual background in biology and computation. His research combines biomolecular NMR, structural biology, and machine learning to study how GPCRs function dynamically. Dr. Thomas Sakmar has run a laboratory at Rockefeller University for roughly thirty years. His group contributed to the early cloning of GPCRs in the mid-1980s and has since pushed the boundaries of GPCR biochemistry — including early homology modeling, coarse-grained molecular dynamics, and genetic code expansion for site-specific chemistry on receptors. Dr. Tudor Oprea is Principal Investigator at the University of New Mexico and coordinator of the Illuminating the Druggable Genome Knowledge Management Center. An MD-PhD who has practiced machine learning since 1989, he built Pharos, the public-facing data platform for the IDG program, and co-developed G1, the first agonist for GPR30, which reached an IND for melanoma. Scientific Themes of the Conversation The definitional boundary between AI, machine learning, and computational modeling Data quality as the rate-limiting step for machine learning in GPCR pharmacology Orphan receptor deorphanization and the limits of learning from known peptides Generative models, scoring functions, and the role of molecular dynamics in ligand design The true-negatives problem and how it distorts biological models The hybrid future: chemical intuition, experimental judgment, and where computation still falls short Key Insights from the Conversation AI and machine learning are not the same thing, and the difference matters. Machine learning finds patterns in defined datasets; AI aims to substitute for human reasoning more broadly. Using the terms interchangeably blurs what each approach can realistically deliver in a pharmacology workflow. The barrier isn't messy data — it's missing metadata. Most pharmacology datasets aren't useless for ML; they're incomplete. Buffers, incubation temperatures, time points, co-expression conditions, the specific Emax reference — these are the details that determine whether a dataset can be pooled with others or must stand alone. Deorphanization via AI is possible, but constrained by what we already know. Random-forest classifiers trained on known peptide ligands can find new orphan-receptor pairings. But the remaining orphans may be orphans precisely because they don't resemble anything we've characterized — which caps what this class of model can find. The bottleneck in structure-guided ML isn't the algorithm. The panel agreed that the real limits are the availability of high-resolution GPCR structures and the computational cost of molecular dynamics simulations needed to capture the dynamic conformations behind signaling. True negatives quietly wreck biological models. Most published models rely on inferred negatives — genes or molecules assumed inactive by convenience. When one panelist replaced inferred negatives in an autophagy model with CRISPR-validated true negatives, the model's predictions changed radically. Chemical intuition has no AI equivalent yet — and won't soon. The experience of a seasoned medicinal chemist mentally docking a molecule from a 2D structure is not a skill current models replicate. The panel expects a hybrid future, not a replacement one, for the next five to ten years. Olfactory GPCRs remain a trillion-dollar opportunity the field has largely ignored. GPCR-targeting drugs represent roughly 0.9 trillion dollars in global sales across 75 countries. Olfactory GPCRs — which account for a large fraction of the receptor class — have been systematically sidestepped for lack of tractable in vitro screening methods. Episode Timeline 00:00 Welcome from Yamina Berchiche 01:36 Panelist introductions 11:41 AI vs machine learning — the definitions that matter 15:21 The undrugged majority: 400 non-olfactory GPCRs, only 160 drugged 20:12 What makes a pharmacology dataset usable for machine learning 24:41 Advice for small academic labs entering the field 30:34 Can AI help deorphanize understudied receptors? 37:01 Reading GPCR signaling dynamics with computational models 39:53 Generative models, scoring functions, and molecular dynamics 50:32 The true-negatives problem and the limits of inferred datasets 52:30 Hype vs reality in AI drug discovery 55:05 Where the GPCR field goes in the next five years Timestamps were generated using AI for readability. Selected Quotes "My computational team told me, 'this receptor is not using arrestin to internalize. There has to be an arrestin-independent thing there.' And I'm like, that's rubbish. Never picked it up. Complete rubbish. And then a year later or so, I get a call from a colleague who said, 'oh, we've tested this compound as a negative control because we thought it doesn't need arrestin to internalize. And now we put it in this CRISPR knockout cell and — it does.'" — Dr. Maria Waldhoer "In 1989, as a med student in Romania, I used BASIC to model the variation in heart rate and blood pressure for 11 patients. I wrote an 11 polynomial that fit everything, so I thought I had solved the problem with drug discovery. I have learned a lot since." — Dr. Tudor Oprea "Dan Rich worked on HIV protease inhibitors. He would look at the 2D structure and basically mentally do a docking and tell you whether that's a good protease inhibitor or not. I think there are people who have worked in the GPCR field that can do a similar exercise." — Dr. Tudor Oprea "If you only make big enough numbers, big enough networks, big enough algorithms, suddenly intelligence pops out on the other side. [Roger Penrose] said, well, it's simply because they cannot think of anything else to do yet." — Dr. Maria Waldhoer About this episode Listen to this fantastic round table discussion that I had the privilege to moderate with Alexander Hauser . Our guests were Maria Waldhoer , Tudor I. Oprea , Thomas Sakmar , Aurelien Rizk & Yaroslav Nikolaev . The explosion of biomedical data such as in genomics, structural biology, and pharmacology can provide new opportunities to improve our understanding of human physiology and disease. In recent years, machine learning (ML) and artificial intelligence (AI) methods have received a significant boost in attention. ML/AI can be powerful for identifying abstract patterns within large data where traditional methods would be oblivious to. This comes without the need for manual feature engineering as systems can learn through implicit rules from the data provided. G protein-coupled receptors (GPCRs) mediate a vast variety of critical biological processes and provide an ideal case study for quantitative, and multi‐scale integration of these amounts of data to gain novel insights into receptor biology. How can we best leverage these exciting new techniques in areas such as protein structure prediction, bioactive ligand discovery, in-vivo translation ability, or in our understanding of signaling determinants? Here, we would like to discuss the opportunities, weaknesses, and advantages of these new technologies, which may contribute to probe our favorite targets at all scales. For more information on the ERNEST network, visit https://ernest-gpcr.eu/ . Dr. Yamina Berchiche on the web 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. Oliver Hartley About Dr. Oliver Hartley Oliver Hartley is VP for Drug Discovery at Orion Biotechnology . He is the inventor of OB-002 as well as the key technology underlying Orion’s discovery platform. Trained as a biochemist, he completed a PhD in protein engineering (Cambridge, UK) with Sir Gregory Winter (Nobel Prize for Chemistry, 2018). Since then Oliver has worked at the University of Geneva, where his research on peptide engineering and GPCR pharmacology has led to a series of high-profile publications and new intellectual property, and at the Mintaka Foundation for Medical Research with a role as co-founder and Chief Scientific Officer. Dr. Oliver Hartley on the web LinkedIn Orion Biotechnology 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. Lukas Grätz About Dr. Lukas Grätz "After a BSc in biology and a MSc in bioinformatics, I have been working in David Gloriam's group as a bioinformatician. My initial focus was on creating an automated chimeric homology modeling pipeline for GPCRs and since have branched out to multiple areas of GPCR research such as sequence alignments, generic numbering systems, structure data, G protein and arrestin coupling and more. As a developer, and more recently the lead developer of GPCRdb my day-to-day work centers around the maintenance and resource/tool development of GPCRdb and its sister databases. I am also affiliated with György Keserű's group at the RCNS in Hungary. I lived in Denmark, Poland, now I live in Hungary. I am married, I have two daughters. In my free time I like to play the guitar, sing and play board games. " Dr. Lukas Grätz on the web Karolinska Institutet ResearchGate PubMed 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 Your GPCR Order Has Arrived! ❇ Feb 10 - 16, 2025 🚀 GPCR Pals, Get Ready to Elevate Your Expertise! Welcome back to your exclusive GPCR Weekly Newsletter! We’re thrilled to unveil our ever-expanding course roster—designed to help you stay at the cutting edge of GPCR research. New topics, expert-led sessions, and hands-on learning opportunities await! 🎓 Kicking Off Today: Dr. Terry Kenakin ’s hands-on workshop, The Practical Assessment of Signaling Bias . Didn’t sign up? Don’t worry— registrations are NOW OPEN for the 2025 Dr.GPCR University Courses! This is your chance to learn directly from our world-renowned experts. Come back regularly as we are adding courses each month. Email us if you'd like to teach or if you'd like to learn more about any particular topic. 🗓️ Upcoming 4-Week Course: Development of GPCR Ligands as Therapeutic Drugs starting March 20 – April 10, 2025 (Thursdays, 10:00 AM–12:00 PM EST). Watch Dr. Kenakin as he introduces the key concepts of this brand-new course. During these four sessions, you'll dive into: Advanced pharmacokinetic modeling The Druglike Quality of Chemical Entities Drug Absorption 💡 Looking for workshops? We’ve got you covered! ✅ Practical Quantification of Allosteric Modulation – May 1, 2025 ✅ Applying the Black/Leff Operational Model to Predict Agonism – October 2, 2025 Premium Members save 25% on enrollment. Reserve Your Spot Now! 🔗 Register Today . 🔥 Act Fast – Only 25 Spots Available! ⚡ Don’t miss out! Premium Members save 25% on enrollment! Secure your spot today! Highlights of the Week How Ligands Achieve Biased Signaling toward Arrestins Stéphanie Gaillard , Neha Verma , Leisha A Emens , et. al. A combined in silico approach to design peptide ligands with increased receptor-subtype selectivity Adam Zech , Victoria Most , René Staritzbichler , et. al. A2B adenosine receptor-triggered intracellular calcium mobilization: Cell type-dependent involvement of Gi, Gq, Gs proteins and protein kinase C Qin Wang , Wenwen Hao , Jing Li , et. al. Classified GPCR News Let’s dive into the Classified GPCR News from February 10th to 16th, 2025 Industry News Pain targets in ion channel pathways: an Innovation Distillery spotlight ‘It’s not for the faint of heart.’ How 3 CEOs took their biotechs public Aikium's AI-Driven mRNA Engine Looks to Address Undruggable Disordered Proteins Tectonic Therapeutic Secures Massive $185M PIPE Financing for Clinical Programs Septerna Announces Discontinuation of SEP-786 Phase 1 Clinical Trial and Plans to Advance Next-Generation Oral Small Molecule PTH1R Agonist Call for GPCR Papers NEW Special Issue on Adhesion GPCRs GPCR Events, Meetings, and Webinars March 19, 2025 | Advancing obesity drug discovery: Cell-based assays for GLP-1 and the G-Suite March 17 - 21, 2025 | 2nd GPCR signaling and drug discovery Symposium & Workshop NEW April 2 - 3, 2025 | New therapeutic modalities: Transforming receptor pharmacology April 3 - 6, 2025 | ASPET 2025 April 24 - 27, 2025 | American Physiology Summit 2025 April 25 - 30, 2025 | AACR Annual Meeting 2025 May 12 - 15, 2025 | PEGS 2025 May 15 - 17, 2025 | 23rd GPCR Retreat 2025 May 20 - 22, 2025 | SLAS Europe 2025 NEW May 20 - 22, 2025 |4th GPCRs-Targeted Drug Discovery Summit June 22 - 26, 2025 | G Protein-coupled Receptor Kinases and Arrestins NEW December 16 - 18, 2025 |Pharmacology 2025 July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology GPCR Jobs Structural Biologist Associate Director/Director, Platform & Hit-ID Chemistry Lead Junior associate position and a PhD/post-doc level position Postdoctoral Position And PhD Position GPCR Molecular Pharmacologist Scientist - Biology Scientist I Cell Biology - Tectonic Therapeutic Senior Principal Scientist, Medicinal Chemistry PhD fellowship in GPCR mechanosensing GPCR Activation and Signaling Lineage-Specific Class-A GPCR Dynamics Reflect Diverse Chemosensory Adaptations in Lophotrochozoa β-arrestin 1 and integrin-linked kinase interact in epidermal keratinocytes and regulate cell motility The regenerative wound healing effects and molecular mechanism of Isaria cicadae Miquel rice fermentation extract A2B adenosine receptor-triggered intracellular calcium mobilization: Cell type-dependent involvement of Gi, Gq, Gs proteins and protein kinase C GPCRs in Cardiology, Endocrinology, and Taste N-homocysteinylation of β-arrestins biases GPCR signaling and promotes platelet activation GPR180 Reduces Adiposity by Inhibiting Lipogenesis and Fatty Acid Uptake in Adipocytes Derivation of hiPSC line (ICADRB2i007-A-3) from an individual with osteoporosis linked to ADRB2: c.46G > A GPCRs in Neuroscience Effects of chemogenetic virus injection and clozapine administration in spinal cord injury GPR37L1 identifies spinal cord astrocytes and protects neuropathic pain after nerve injury Hypothalamic opsin 3 suppresses MC4R signaling and potentiates Kir7.1 to promote food consumption Reviews, GPCRs, and more How Ligands Achieve Biased Signaling toward Arrestins Structural and Molecular Insights into GPCR Function A combined in silico approach to design peptide ligands with increased receptor-subtype selectivity Ligand-Independent Spontaneous Activation of Purinergic P2Y6 Receptor Under Cell Culture Soft Substrate 🔎 GPCR KEYWORDS Class-A G protein-coupled receptors , Lophotrochozoa , echinoderms , Arrestins , ILK , directional migration , epidermis , keratinocytes , scaffold proteins , β-arrestin , Hippo pathway , IMFRE gels , Regenerative healing , Skin repair , Wound healing , A2B adenosine receptor , Calcium , G protein , GPCR , Gi , Gq , Gs , N-homocysteinylation , Adiposity , Fatty Acid Uptake , Lipogenesis , Induced pluripotent stem cells , Osteoporosis , Reprogramming , AAV5-hSyn-hM3Dq-eYFP , Clozapine , DREADDs , Gq signaling pathway , Neuroregeneration , EPSC , GLT-1 , GPR37L1 , SPM , astrocytes , maresin 1 , microglia , nerve injury , neuropathic pain , spinal cord dorsal horn , OPN3 , cAMP signalin g , MC4R , docking , opioid , peptide ligand design , protein design , Ca2+ oscillation , GPCRs , basal activity , purinergic receptor , substrate stiffness < Previous Next >

< Back Fresh, Fresh, GPCR News ❇ Feb 17 - 23, 2025 Hi friends! Welcome to our weekly update! This week's GPCR roll-up includes the latest insights, research discoveries, and advancements. We'll also preview upcoming courses designed for both experienced researchers and newcomers. 🚀 Develop New GPCR Skills Join Dr. Terry Kenakin’s unique course, Development of GPCR Ligands as Therapeutic Drugs , and gain essential insights into: 🔹 Drug Development Basics – PK-PD insights, absorption, and drug properties 🔹 Clearance & Metabolism – Distribution, renal/hepatic pathways, and elimination 🔹 Safety First – Identifying toxicity risks and drug-drug interactions ⏳ Availability is limited. Register now and shape the future of drug discovery! Premium Members enjoy a 25% discount Secure Your Spot Today! Tune in to Ep.160 of the Dr. GPCR Podcast 🎧 Join Remi Janicot as he shares his educational journey, passion for basketball and science, and career decisions. He discusses biased signaling in GPCR research, developing biosensors for G protein activity, networking, mentorship, PhD resilience, COVID-19 challenges, and his aspiration to transition into biotechnology investment opportunities. Highlights of the week Structural insights into prolactin-releasing peptide receptor signaling and G-protein coupling selectivity Zhangsong Wu , Chen Qiu , Geng Chen , et al. Single-Molecule Insights into GPCR Conformational Landscapes Rajan Lamichhane Discovery of CCR8 Antagonist IDOR-1136-5177 for the Treatment of Cancer Stefan Diethelm , Luboš Remeň , Olivier Corminboeuf , et al. Classified GPCR News Let’s dive into the Classified GPCR News from February 17th to 23rd, 2025 Industry News Septerna Announces Discontinuation of SEP-786 Phase 1 Clinical Trial and Plans to Advance Next-Generation Oral Small Molecule PTH1R Agonist Revolutionizing Protein-Ligand Simulations: OpenMMDL's Open-Source Approach The Rapid Push into Radiopharmaceuticals in Oncology and What’s Next Call for GPCR Papers Special Issue on Adhesion GPCRs GPCR Events, Meetings, and Webinars March 19, 2025 | Advancing obesity drug discovery: Cell-based assays for GLP-1 and the G-Suite - Online March 17 - 21, 2025 | 2nd GPCR signaling and drug discovery Symposium & Workshop - Brazil NEW April 1 - 3, 2025 | 2nd Peptide-Based Therapeutics Summit - USA April 2 - 3, 2025 | New therapeutic modalities: Transforming receptor pharmacology - UK April 3 - 6, 2025 | ASPET 2025 - USA NEW April 14 - 17, 2025 | 20th Drug Discovery Chemistry 2025 - USA April 24 - 27, 2025 | American Physiology Summit 2025 - USA April 25 - 30, 2025 | AACR Annual Meeting 2025 - USA NEW May 1 - 2, 2025 | 5th Ace Drug Discovery Summit 2025 - USA NEW May 12 - 15, 2025 | ACSMEDI-EFMC Medicinal Chemistry Frontiers 2025 - USA May 12 - 15, 2025 | PEGS 2025 - USA May 15 - 17, 2025 | 23rd GPCR Retreat 2025 - USA May 20 - 22, 2025 | SLAS Europe 2025 - Germany May 20 - 22, 2025 |4th GPCRs-Targeted Drug Discovery Summit - USA June 22 - 26, 2025 | G Protein-coupled Receptor Kinases and Arrestins - USA December 16 - 18, 2025 |Pharmacology 2025 - UK July 12 - 17, 2026 | 20th World Congress of Basic and Clinical Pharmacology - Australia GPCR Jobs NEW Open Postdoctoral position - Stanford University Structural Biologist - Confo Therapeutics Associate Director/Director, Platform & Hit-ID Chemistry Lead - Septerna Junior associate position and a PhD/post-doc level position - Eli Lilly and Company Postdoctoral Posit ion And PhD Position - Autonomous University of Barcelona GPCR Molecular Pharmacologist - Schrödinger Scientist - Biology - Superluminal Medicines Scientist I Cell Biology - Tectonic Therapeutic Adhesion GPCRs A force-sensitive adhesion GPCR is required for equilibrioception GPCR Activation and Signaling Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR Light intensity-dependent arrestin switching for inactivation of a light-sensitive GPCR, bistable opsin Diapause hormone receptor affects larval growth and embryonic development in the multivoltine strain of Bombyx more Profiling Allosteric Modulators of CB1R with an Allosteric Fluoroprobe GPCRs in Cardiology, Endocrinology, and Taste Immunolocalization and quantification of the phoenixin and GPR173 in the gastrointestinal tract of Holstein-Friesian bulls Derivation of hiPSC line (ICADRB2i007-A-3) from an individual with osteoporosis linked to ADRB2: c.46G > A GPCRs in Neuroscience Cortical astrocyte activation triggers meningeal nociception and migraine-like pain GPCRs in Oncology and Immunology Spatial analysis of a complete DIPG-infiltrated brainstem reveals novel ligand-receptor mediators of tumour-to-TME crosstalk Discovery of CCR8 Antagonist IDOR-1136-5177 for the Treatment of Cancer The extracellular matrix protein type I collagen and fibronectin are regulated by β-arrestin-1/endothelin axis in human ovarian fibroblasts Methods & Updates in GPCR Research Histamine-modulated wettability switching in G-protein-coupled receptor inspired nanochannel for potential drug screening and biosensing Reviews, GPCRs, and more Single-Molecule Insights into GPCR Conformational Landscapes Covalent functionalization of G protein-coupled receptors by small molecular probes A deadly taste: linking bitter taste receptors and apoptosis Molecular roles in membrane receptor signaling pathways and cascade reactions in chondrocytes: a review Is GCR1 the GPR157 of plants? Structural and Molecular Insights into GPCR Function Structural insights into prolactin-releasing peptide receptor signaling and G-protein coupling selectivity Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor 🔎 GPCR KEYWORDS GPCR , structural biology , biased signaling , metabolism , Chondrocytes , Signaling pathway , Integrin , Taste family 2 receptors , Calcium , Cell death , Mitochondria , macrolide antibiotics , motilin receptor , azithromycin , Extraoral taste receptors . < Previous Next >

Discover top GPCR Courses for your educational journey. Explore a curated list of GPCR Courses to enhance your knowledge and career. Stay at the Forefront of GPCR Drug Discovery Gain insider methods from the pioneers shaping biased signaling, assay design, and pharmacology—skills you won't find in any textbook or paper. ⧖ 20+ Hours of Expert Training ↓ Downloadable Resources ◕ New Courses added Quarterly Get Access to GPCR Courses Learn in 3 Simple Steps Free trailers coming soon Preview every masterclass before joining Unlock full access Get Premium for complete library access Learn anytime, anywhere Access on-demand from any device Join Premium Today Unlock Insider Access to GPCR Science! Free updates, exclusive previews, and highlights from our Masterclasses and Vault. First name Last name Email* Join Our Mailing List Count me in! * Explore the Masterclasses Trailers are free. Full classes require Premium. Filter by Category Filter by Level Filter by Instructor Watch Now INSTRUCTOR Heading 5 I'm a paragraph. Click here to add your own text and edit me. It's easy. Read More INSTRUCTOR Heading 5 I'm a paragraph. Click here to add your own text and edit me. It's easy. Read More INSTRUCTOR Heading 5 I'm a paragraph. Click here to add your own text and edit me. It's easy. 1 2 3 4 5 1 ... 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 ... 100 Learn directly from world leaders in GPCR research Access exclusive training from the scientists shaping the future of GPCR drug discovery Dr. Terry Kenakin Terry's Corner Author of 'A Pharmacology Primer', the definitive GPCR reference used by labs worldwide. Former GSK principal research investigator with 40+ years of industry experience. Dr. Sam Hoare Pharmechanics GPCR signaling & biased agonism expert regularly consulted by top pharma companies for assay design strategies. Pioneer in quantitative pharmacology methods. Dr. Yamina Berchiche Dr. GPCR Community builder for scientists with expertise in GPCR project strategy and translational applications. Unlock All 20+ GPCR Masterclasses – Save 95% Individual courses cost $300–600 each. With Premium, you get everything for just $249.99/year (less than $1/day). 20+ Hours of GPCR Masterclasses Downloadable Resources & Q&A Replays Weekly GPCR Insights (papers, jobs, events) Networking with a global scientist community One failed assay can cost $10,000+ in reagents and months of time. Think of Premium as insurance against wasted experiments and failed drug leads. Best Value Premium Yearly $249.99 $ 249.99 Every year 🚀 Everything you need to master GPCR science — in one membership. Valid until canceled Join Premium Now 🎓 Full GPCR University + 🔬 200+ expert talks 🗞️ Weekly research, careers & event intelligence 🤝 Members-only networking, AMAs & matchmaking 💡 Support open resources for the global GPCR field 🧠 Designed for researchers at every career stage 🚀 Don’t just keep up — lead the way. What Scientists Are Saying Dr. Hoare is very experienced in the field. What came as a pleasant surprise was how didactical and well-thought-out his course was—highly recommended. The really unexpected was that the Q&A sessions reached the highest level—beyond excellent. I am a convert! I will keep Dr. GPCR and the offered resources in my work sphere Anonymous Thank you for bringing this course with Dr. Kenakin. I wish Dr. GPCR the best for the sake of promoting more educational opportunities that are sorely needed in the field Anonymous The content had enough depth to satisfy the hunger for theory while being full of practical knowledge Anonymous The best pharmacology teacher teaming up with the best GPCR community platform to help train and inspire the next generation of scientists. Also super-valuable for those of us learning how to teach pharmacology Anonymous Dr. Hoare's extensive and elaborative explanation of the topics at hand was excellent and very digestible. Thoroughly enjoyed learning from him Anonymous Dr. Kenakin is a leading expert in the field. Aside from his vast experience in drug development, not to mention his extensive publication record, Dr. Kenakin is a masterful teacher and communicator. Anonymous What are the benefits of becoming a member of Dr.GPCR? As a member, you can access: Dr.GPCR Podcast videos Live GPCR events Weekly classified GPCR news Contributor articles As a premium member, you can access all the free features plus: GPCR courses with a 25% discount Private groups 30+ Symposia recorded talks GPCR Job listings GPCR Event listings Direct access to members of the GPCR community How do I sign up for a membership? To sign up, click the 'Log In/Sign Up' button at the top of the homepage and fill out the registration form. Once your registration is complete, you will receive a confirmation email. Why do I need to fill out a form and wait for approval? We carefully screen anyone signing up to the Ecosystem to ensure they are real humans working on GPCRs. We want to keep our community exclusive to the field, so we need as much information as possible to verify your identity. How long will the Sign-Up process take? We could take up to two (2) business days. I’m just a student starting in the field. 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The Practical Assessment of Signaling Bias Dr. Terry Kenakin < Back Workshop Summary Join Dr. Terry Kenakin , a leading expert in pharmacology, as he unpacks the fascinating world of signaling bias in drug development! 🚀 This workshop will explore how different ligands (compounds) can stabilize unique receptor conformations, leading to distinct signaling outcomes—even when binding to the same receptor. Dr. Kenakin will explain that bias is not an exception but a fundamental principle of pharmacology, occurring whether or not researchers actively seek it. Through an engaging discussion, you'll explore: 🔹 What signaling bias is and why it matters 🔹 How receptor dynamics shape drug responses 🔹 Cutting-edge methods for quantifying bias 📊 🔹 Strategies to harness bias for better drug design —maximizing efficacy while minimizing side effects The session wraps up with a lively Q&A , allowing attendees to explore this game-changing topic in greater depth. Don't miss this opportunity to refine your understanding of bias as a tool, not an obstacle, in pharmacology! Key Highlights 🔍 Bias is Everywhere : Signaling bias naturally occurs in pharmacology—whether we look for it or not! 🧬 Receptor Flexibility : Ligands stabilize different receptor states, creating unique signaling pathways. 📏 Measuring Bias : New techniques allow us to quantify bias and compare drug efficacy more precisely. 💊 Therapeutic Potential : Understanding bias enables researchers to design drugs that target specific effects while avoiding unwanted side effects. 🗣️ Interactive Q&A : The discussion wraps up with an insightful Q&A, tackling real-world drug development challenges. Deep Dives & Insights 📌 Bias is Not an Anomaly—It’s a Feature! 🔹 Instead of avoiding bias, researchers can embrace it to refine drug responses. Dr. Kenakin challenges the traditional approach and encourages leveraging bias for better therapeutic outcomes. 📌 Receptors are Dynamic Players 🔹 Different ligands trigger unique receptor states, meaning the same receptor can signal in entirely different ways depending on what binds to it. Understanding these shifts can revolutionize drug development! 📌 Measuring Bias: A Quantitative Approach 🔹 The operational model provides a structured way to measure bias, combining affinity and efficacy. This allows for a side-by-side comparison of how different compounds influence receptor signaling. 📌 Bridging the Gap: Lab to Clinic 🔹 While measuring bias in a lab is relatively straightforward, translating these findings to clinical applications remains a challenge . The talk explores how to navigate this crucial gap. 📌 The Future of Drug Development 🚀 🔹 By integrating bias into drug design , researchers can craft more selective, effective, and safer therapies. This approach is shaping the next generation of precision medicine! Dr. Terry Kenakin’s workshop offers a fresh perspective on drug discovery . It shows that bias isn’t something to avoid—it’s something to utilize ! Whether you're a researcher, student, or industry professional, this session is packed with insights that will make you rethink your approach to pharmacology . Ready to explore the future of biased drug design? Let’s dive in! 🔬✨ AI Summary - May contain inaccuracies Materials: BIAS_WORKSHOP_PRINT .pdf Download PDF • 9.11MB BIAS_EXERCISE .pdf Download PDF • 721KB What would you like to learn today?

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