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Discover the essence of GPCR Retreat, an international GPCR Event that empowers the GPCR field. GPCR Reatreat The GPCR Retreat focuses on advances in our understanding of how GPCRs operate in cell communication. The main goal of the GPCR Retreat is to provide a venue for students, post-doctoral fellows, and principal investigators from academia and industry to discuss and debate existing and novel concepts in GPCR biology. One of the core values of this international meeting is to promote interactions among all participants of all diversity backgrounds, particularly between trainees and principal investigators. Each year, approximately 2/3 of the participants are trainees. Registration to the GPCR Retreat is capped at 200 participants to promote an intimate environment. Most importantly, the GPCR Retreat dedicates time for two trainee symposia, an initiative that began in the Ottawa 2017 edition, to showcase the breadth of diversity in GPCR trainee communities. For the Ottawa 2017 GPCR Retreat, of the ten talks from trainees 80% were from women and 60% from visible minorities. Over the years, the meeting has grown into one of the most recognized international events in the field. That reputation has led to broad participation from the Great Lakes region and beyond. Conference History The GPCR Retreat is an annual joint meeting with the Club des récepteurs à Sept Domaines Transmembranaires du Québec that rotates around locations in Canada and the United States surrounding the Great Lakes region. The first Great Lakes GPCR Retreat was conceived, organized and held in London, Ontario, Canada in October 1999. The following year, the Great Lakes GPCR Retreat partnered with the annual symposium of the Club des Récepteurs à Sept Domains Transmembranaires du Québec. The meeting tours through many of the major universities in the Great Lakes region in both Canada and the United States. The past few GPCR retreats have been held in: - Niagara-on-the-lake (2022) - Bromont, Québec (2019) - Detroit, Michigan (2018) - Ottawa, Ontario (2017) - Chicago, Illinois (2016) - Toronto, Ontario (2015) - Bromont, Québec (2014) - Cleveland, Ohio (2013) London, Ontario (2012) Fairmont Le Château Montebello, Québec, Canada November 2-4, 2023 We are pleased to welcome you at Le Château Montebello, the 22nd Annual Great Lakes G Protein-Coupled Receptor Retreat held jointly with the Club des Récepteurs à Sept Domaines Transmembranaires du Québec. The meeting will be held on Nov. 2-4, 2023 at the Chateau Montebello, Québec. The Chateau Montebello is an exceptional venue, and is located 1 hr from Ottawa, or 1.5 hr from Montreal in the beautiful Laurentian Mountains of Canada. The fall colors of the leaves are spectacular, and the weekend of science is an intense and interactive experience, and a great training environment for our students and post-doctoral fellows. The meeting is launched on Thursday with two Trainee Symposia and the Plenary Lecture, followed by 6 symposia on Friday and Saturday and the closing Keynote Lecture. The deadline for registration is September 21, 2023. For the 22nd edition, the Organizing Committee has again lived up to the expectations by putting together an outstanding program with a special thought for Marc Caron (1946-2022) to commemorate his great contributions to the GPCR and Neurosciences fields. Dr. Kathleen Caron of the University of North Carolina at Chapel Hill, unquestionably one of the pioneers involved in deciphering how receptor activity-modifying proteins or RAMPs regulate GPCR function, is confirmed as Plenary Speaker of the inaugural Marc G. Caron keynote lecture on November 2nd. Additionally, there will be a Marc G. Caron Honorary Symposium by Caron Lab alumni to honor his memory. We have also confirmed Dr. Arthur Christopoulos of Monash University in Australia, one of the pioneers in the medicinal chemistry, computational and mathematical modelling of GPCRs, as Plenary Speaker of the Hyman B. Niznik keynote lecture, which will close the conference. The program will include also world-class and diverse GPCR scientists working in the arenas of structure and signaling, neuroscience, cancer, translational and model systems. As in previous editions, trainees are more than welcome to this unique meeting. Indeed, for the Montebello 2023 edition, we have organized two trainee symposiums to acknowledge formally the participation of our graduate students and post-doctoral fellows. Additionally, each symposium of the GPCR Retreat 2023 will include one trainee short talk selected from abstracts. Trainees of diversity groups are strongly encouraged to register to the meeting and submit an abstract for consideration for the trainee symposia and selected trainee short talks. Your participation has already made this unique event a success. We are thrilled by the overwhelming interest in this event by the GPCR research community. We trust that the collegial and intimate atmosphere provided by Le Château Montebello will be suited for an environment where graduate students, postdoctoral fellows and principal investigators can have stimulating discussions and debates on GPCR research presented at this meeting. We would like to thank all our Sponsors for their ongoing generous support of the meeting. Without their support, this meeting will not be possible. If you have any suggestions or comments for either this Retreat or future meetings, we look forward to receiving your feedback. Finally, Bienvenue and we hope you will enjoy your stay in Montebello and find the Retreat stimulating and satisfying. Sincerely, The Organizing Committee GPCR Retreat Organizers

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

Get ready to connect, collaborate, and innovate at the Dr. GPCR Retreat — an immersive event uniting scientists, biotech leaders, and innovators in GPCR research. Dr. GPCR Retreat - Coming Soon - Please tell us your thoughts about scientific gatherings by filling out this short survey

Discover how Timeline Strategy helps GPCR innovators scale their organizations through strategic planning, effective systems, and operational clarity. Home: Welcome Timeline Strategy x Dr. GPCR — Scaling Biotech Beyond the Bench Turning scientific excellence into scalable organizations. We help GPCR innovators design systems, strategies, and operating frameworks that drive predictable growth. See how we can help you About Timeline Strategy Founded by Attila Foris, Timeline Strategy partners with science-driven teams to bridge the gap between innovation and execution. Our work helps biotech startups, research organizations, and CROs design operating systems that enable clarity, accountability, and scale. Core themes: Strategic Planning for Biotech Growth Operational System Design (OS) Cross-functional Team Alignment Scaling Protocols & Decision Architecture From Chaos to Scale Timeline Strategy built to execute, not decorate slides Most strategies die in PowerPoints. Timeline Strategy lives in execution. In 3 fast steps , we turn your bottlenecks into momentum: 1. Diagnose the mess → where your growth stalls. 2. Build clarity → align people, process, priorities. 3. Scale with confidence → expand without burnout. Building the Strategic Backbone of GPCR Innovation In the rapidly evolving GPCR field, scientific progress alone isn’t enough — sustainable growth requires operational precision. Together with Dr. GPCR, we help organizations: ✅ Clarify vision and direction ✅ Translate research milestones into measurable objectives ✅ Build internal systems and workflows that support scale ✅ Create investor-ready operating structures Our Partners Benefit From: Strategy Audits & Growth Frameworks Operating System (OS) Implementation Leadership Alignment Sessions Scalable Team Protocols & Processes From the Strategy & Operations Blog The Hidden Cost of Ambition in Biotech Leadership 👉 Ambition is the default setting of biotech. Platforms expand. Indications multiply. New opportunities appear constantly. That is not a flaw. It is the nature of scientific possibility. 👉 The problem begins when ambition grows faster than structure. What feels like momentum can quietly become dilution. More programs. Broader roadmaps. Increasing complexity. And slowly, strategic focus weakens . This is the hidden cost of ambition in biotech leadership. Not failure. Not poo Attila Foris Mar 2 The Real Cost of Strategic Overload in Biotech 👉 In early-stage biotech, activity often feels like strategy. The platform is advancing, multiple indications are progressing, a grant application is underway, and early partnership conversations are taking shape. At the same time, the team is preparing for biotech fundraising. On the surface, this looks like a strength. There is movement across the board. Each initiative has logic behind it. Each program appears to increase optionality and reduce risk. 👉 This is where str Attila Foris Feb 23 The Moment Biotech Founders Realize the Money Is Gone 👉 Most biotech founders do not realize they are in trouble when the money runs out. By then, the situation is already decided. 👉 The real issue begins earlier, at a point where the company is still operating, the science is progressing, and milestones are being met. On paper, things look fine. In reality, something more subtle starts to shift. 👉 Decision-making changes. Plans that once felt flexible start to feel constrained. Conversations move from options to assumption Attila Foris Feb 16 1 2 3 4 5 Collaborate with Timeline Strategy Whether you’re leading a GPCR startup, a CRO, or an academic lab ready to scale, Timeline Strategy helps you design clarity into your growth process.

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Browse past events hosted by the Dr. GPCR Ecosystem, featuring scientific meetings, workshops, and collaborations that brought the GPCR community together. Past Events - Where the Dr. GPCR community comes alive Welcome to the page where the heart of the Dr. GPCR community comes alive! Here, we celebrate the incredible moments that brought scientists, researchers, and GPCR enthusiasts together to share groundbreaking discoveries, spark new ideas, and forge lasting connections. From immersive workshops and high-energy summits to intimate retreats and virtual conferences, each event represents a milestone in our shared mission to advance GPCR science and collaboration worldwide. 👉 Dive into our event archive below to relive the energy, inspiration, and community spirit that make Dr. GPCR truly special. Be part of our journey — stay inspired by our collective passion for science, learning, and discovery. Adhesion GPCR Workshop 2024 Endocrine Metabolic GPCRs Meet Inoviem Team GPCR ECI Transatlantic 2022 Editorial: GPCR and G Protein-Mediated Signalling Events in the Nervous System Dr. GPCR Ecosystem 2.0: Collaborating better Dr. GPCR: Advancing GPCR Drug Discovery Through Collaboration Discovery On Target 2024 GPCR targeted drug discovery Summit 2024 GPCR targeted drug discovery Summit 2023 The Dr. GPCR Podcast GPCR targeted drug discovery Summit 2022 Dr. GPCR: Where all GPCRs are created equal Dr. GPCR: Beyond the lab GRS and GRC Switzerland GPCR Retreat 2023 Leadership is a learned skill - PhageMed Unige GPCR Retreat 2022 Dr. GPCR: Beyond the lab Dr. GPCR: From idea to Ecosystem Dr. GPCR: Beyond the lab

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This comprehensive portfolio offers multiple product formats to match your exact needs, whether you're conducting exploratory screens or regulatory-compliant potency testing. Assay Principle of Eurofins DiscoverX Cell-based Assays Whether you are developing small-molecule or biologic therapeutic drugs, Eurofins DiscoverX provides you with a variety of drug discovery and development products with multiple assay types and applications to meet your specific GPCR research needs. Access Product Solutions and Key Resources GPCR Functional Cell-Based Assays - Assessing Biased Signaling of Agonist Access White Paper Discover Your GPCR Solution - Find The Assay for Your Target of Interest Find Your Solutions The Human GPCRome - Obtain Your FREE Wall Poster for Your Laboratory Obtain Wall Poster Access GPCR Cell Line Assays, Ready-to-Use Kits, Mem Preps, & More Shop Products Supporting GPCR-focused Obesity and Diabetes Research Eurofins DiscoverX supports the ongoing obesity/diabetes revolution with the most comprehensive, validated portfolio for obesity and diabetes GPCR targets, including GLP-1, GIP, GCG, MC4, PYY, AMY receptors, and more. Browse products related to your obesity/diabetes target of interest: CALCRL and RAMP (AMs) GIPR GLP-1R GLP-2R GCGR GPR75 MC4R NPY2R (PYY) SSTR5 Activins CALCR and RAMPs (AMYs) Apelin (APJ/AGTRL1) View representative data: GLP-1R multi-MOA profiling Eurofins DiscoverX's GLP-1 receptor (GLP-1R) assay portfolio illustrates a comprehensive approach to obesity research, with complete MOA coverage for a single target: GLP-1. These assays enable complete pharmacological profiling across cAMP, β-arrestin, and internalization. GLP-1R representative assay results (dose-response curves) for exendin-4, tirzepatide, and retatrutide. A. cAMP dose–response; B. β-arrestin recruitment showing ligand bias; and C. Internalization profiles distinguishing highly versus weakly internalizing agonists. Together, these datasets exemplify the depth of pharmacological insight enabled by Eurofins DiscoverX platforms. This multi-dimensional characterization extends across our full obesity and diabetes product portfolio, including GIPR, GCGR, AMY receptors, MC4R, and beyond. Access GPCR Obesity and Diabetes Solutions and Key Resources Discover GPCR Obesity and Diabetes Product Solutions Find Your Solution Review GIP Product Solutions to Support Obesity/Diabetes View GIP Solutions Explore GLP-1 Product Solutions to Support Obesity/Diabetes See GLP-1 Solutions Accelerating Obesity Therapeutics Development Download App Note Beyond Eurofins DiscoverX Products: The Full Power of Eurofins Discovery Eurofins DiscoverX cell lines, assays, kits, and custom product solutions represent the foundation of tools for GPCR research and drug discovery and development. When these product solutions are combined with Calixar GPCR membrane proteins and Eurofins Discovery GPCR services, the benefits from integration provide the most comprehensive GPCR research and drug discovery platform spanning the entire discovery and development continuum. Eurofins Discovery GPCR services provides the industry's most extensive collection of validated GPCR assays with hundreds of binding and functional assays, available individually or in panels. These assays use the same platform as the Eurofins DiscoverX assays and beyond. Calixar GPCR membrane proteins , as a service, provides a wide array of GPCRs from various species, purified to the highest standards to ensure purity, integrity, and biological activity. These GPCRs are excellent for use in functional, structural, or identification assays. Let us Help You Get Started! Contact us Visit GPCR Product Solutions

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

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<< Back to podcast list Strategic Partner(s) Dr. Daniel Isom About Dr. Daniel Isom "Dan was born and raised in the Cleveland area. He is a first-generation college graduate and academic. After spending two years at the Cleveland Institute of Art, he earned degrees in Biochemistry and Chemistry from Case Western Reserve University. He then went on to earn a Ph.D. in Molecular Biophysics from Johns Hopkins University, followed by postdocs at both Duke University and UNC Chapel Hill. Dr. Isom was recruited to the Molecular and Cellular Pharmacology Department at the University of Miami Miller School of Medicine in 2016, where he is currently a practicing molecular pharmacologist and biophysicist, systems and synthetic biologist, technologist, heavy CRISPR user, protein sequence- and structure-based informaticist, computational geometer, virtual screener, and Python, medical, and graduate educator leading a talented and multidisciplinary research team. " Dr. Daniel Isom on the web Isom Lab University of Miami Miller School of Medicine LinkedIn X (Twitter) BlueSky 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 >>

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Terry Kenakin on how allostery and biased signaling rewrote receptor pharmacology, and why the assay always decides what pharmacologists get to see. << Back to podcast list Strategic Partner(s) Terry Kenakin: Allostery, Bias, and the Assays That Changed What We Could See SCIENTIFIC ABSTRACT Receptor pharmacology spent decades describing a drug as if a single number could carry it: one potency, one efficacy, one response per receptor. Terry Kenakin's career tracks what happened when that picture came apart. Trained first as a chemist in Edmonton and then as a pharmacologist, Kenakin spent more than thirty years in drug discovery at Burroughs Wellcome and through the Glaxo iterations. A CCR5 screen for HIV entry returned an allosteric hit and pushed an entire program into learning allostery the hard way. This conversation follows the thread from that hit through probe dependence to biased signaling, and to the argument that neither is new. Proteins have always moved and always chosen their partners. Pharmacology simply lacked the assays to notice. Kenakin is direct about what the field still cannot do, particularly the distance between a clean bias measurement in cells and a compound that behaves predictably in a person. He also describes flying back to London to show James Black the lab he had built, and being asked a single question about kinetics that reset everything he thought he had finished learning. ABOUT TERRY Terry Kenakin is a professor in the Department of Pharmacology at the University of North Carolina School of Medicine in Chapel Hill. He works on receptor pharmacology, allosteric protein function, and drug discovery, with a long focus on how drug activity should be quantified so that the numbers travel between systems rather than describing only the cells they came from. Before UNC he spent seven years at Burroughs Wellcome and twenty five years across Glaxo Inc, GlaxoWellcome, and GlaxoSmithKline, where he led a CCR5 entry inhibitor program for HIV and worked on chemokine receptors, MC4R, and GLP1. He continues to consult with industry on allosteric programs. He is also the author of A Pharmacology Primer, now in preparation for its sixth edition, a book he describes writing largely to teach himself the field as it kept changing. SCIENTIFIC THEMES OF THE CONVERSATION - Allostery and probe dependence as ordinary protein behavior rather than special cases - Biased signaling, and why it looked rare only while the assays were blind to it - Chemokine receptor redundancy reconsidered as fine tuning - Targeting a single protein versus screening the whole phenotype - Translation: why bias is easy to measure and hard to carry into a body - Building a scientific career across industry and academia KEY INSIGHTS FROM THE CONVERSATION The field did not discover allostery. It acquired the eyes to see it. Kenakin points out that enzymologists were years ahead of pharmacologists on allostery, and that the delay was technological rather than conceptual. Screens were built on binding, so they returned compounds that worked by steric hindrance. Once functional screening arrived, allosteric hits started appearing everywhere they had presumably always been. Bias is what proteins do, not an exception to what proteins do. A protein has a shape, the shape dictates which partners it engages, and a ligand that alters the shape alters the interaction. Kenakin frames probe dependence as the mechanism and biased signaling as the name pharmacology later gave it. He now expects a screen to return compounds that signal differently from the natural hormone, rather than treating such a compound as a curiosity. An allosteric hit dragged one HIV program into years of hard schooling. The CCR5 program at Glaxo found an allosteric compound in the early nineties, and Kenakin describes the two years that followed as the allosteric school of hard knocks: exhilarating, frustrating, and baffling to the chemists who depended on consistent answers from the biologists. The compound, aplaviroc, lowered viral load and reached humans before failing in phase three on liver toxicity. The program still reshaped how he thinks about protein function. Redundancy in the chemokine system turned out to be resolution. Twenty some receptors and roughly fifty chemokines were long read as a fail safe arrangement. Kenakin points to work from Trudy Kohout in the Lefkowitz lab showing that CCL19 and CCL21 act differently at CCR7, one recruiting arrestin and one not. What looked like duplication was nature using bias for fine tuning. The aha moments ran in the opposite direction from the phrase. Reading the Spengler work on PACAP analogs that reversed potency across pathways, Kenakin found something his training could not accommodate. Seeing that a drug could carry more than one efficacy, he says, shattered a model he had felt secure in. He is unusually plain about what this felt like: not the relief of finally seeing, but the recognition that his world had been too simple. Quantifying bias is the easy half. The body is the hard half. Kenakin describes an entire evening session at a Gordon conference spent on the translation problem, with no resolution. Two compounds can be cleanly separated in a simple assay and then meet an in vivo environment that adds nuances nobody modeled. That gap, he argues, is where drugs fail, and closing it is the work that actually matters for making better ones. Fragile nodes, not obvious targets. Knock out an overexpressed kinase and a tumor may simply route around it. Kenakin describes systems as collections of nodes, some redundant and some fragile, and puts the case for phenotypic screening as an attempt to find the fragile ones. He is careful to say this is not his own expertise, which is itself part of the point: the question has outgrown the era he was trained in. SELECTED QUOTES "Research is a privilege, it isn't a right." "He said, yes, but do you know anything about kinetics? And I said, no, I don't. Then you know nothing." "It isn't an aha, now I see. It's an oh, now I don't see." "I expect a screen to give you a compound that will in some way be biased differently from the natural hormone. I expect it, because that's what proteins do." EPISODE TIMELINE Timestamps were generated using AI for readability. - 00:00 Introduction - 02:19 Chemistry in Edmonton, and the Scotsman who said make them drugs - 05:45 Why research is a privilege rather than a reward for good marks - 08:37 Thinking like a chemist inside the vagaries of biology - 12:15 Drafted into CCR5, and the allosteric school of hard knocks - 18:28 Probe dependence, bias, and what proteins were always doing - 22:09 New assays, new eyes, and a richer array of options than expected - 24:55 Chemokine redundancy, CCR7, and why GLP1 is the favorite - 30:10 Dinner with James Black and one question about kinetics - 34:31 Single targets, fragile nodes, and the tumor that laughs at you - 51:10 Are GPCRs still good targets, after being declared mined out - 01:01:36 Advice for early career scientists on industry, ego, and technique - 01:12:07 The aha moments that took certainty away - 01:15:13 Work, life, and a limit you have to set yourself GUEST LINKS - LinkedIn: https://www.linkedin.com/in/terry-kenakin-6634a43b/ - UNC Department of Pharmacology: https://www.med.unc.edu/pharm/directory/terry-kenakin-phd/ - Amazon: https://www.amazon.com/Terry-Kenakin/e/B01I2QNYWO/ - ResearchGate: https://www.researchgate.net/profile/Terry-Kenakin - PubMed: https://pubmed.ncbi.nlm.nih.gov/?term=Kenakin+T - Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/search?q=Terry+Kenakin 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. 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 AI-generated content may be inaccurate or misleading. Always check for accuracy. Quick recap Yamina and Arthur from Monash University discussed Arthur's career journey, the importance of hard work, failure, and differentiation in academic and personal lives, and the value of international conferences. They also explored the significance of translating fundamental discoveries into clinical applications, the potential of new drugs, and the unique challenges within universities. Additionally, they discussed the importance of hiring based on differentiation, impact, and interest, the need for workforce development, and the potential of involving junior scientists and postdocs in their podcast. Lastly, they touched upon the global challenges of healthcare workforce growth, climate change, and emerging psychiatric disorders, as well as the importance of recording lectures and making pre-lesson materials available to students. Next steps - Yamina will share notes about PRISM and presentability with Arthur. - Arthur will share the story of PRISM's development and its impact on the field with Yamina. - Yamina will send an invite for a follow-up meeting with Arthur next Saturday at 9 PM. - Arthur and Yamina will prepare for the next meeting, focusing on the concept of biased agonism and discussing Dr. GPCR and the charity status. - Yamina will attempt to book Denise for a future podcast episode. Summary Arthur's Career Journey and Transition to Dean Yamina introduced Arthur to her team and discussed the use of a particular tool for meeting summaries. Arthur shared his career journey from pharmacy to becoming a professor, highlighting the influence of his mentors and the importance of his postdoctoral experience. They discussed the value of hard work, failure, and the significance of differentiation in their personal and academic lives. Towards the end, they focused on Arthur's transition to become Dean and his decision to move from Australia to the United States for a postdoctoral position. Postdoctoral Position, Scientific Dynamics, and New Drug Targets Arthur shared his decision to undertake a postdoctoral position with Nigel Bird's lab in the UK and his experiences of meeting influential figures during his time in the US. He and Yamina discussed the importance of preserving original work, the value of international conferences, and the dynamics between junior and senior scientists in a research environment. They also shared their admiration for the work of a mutual friend and discussed the history of muscarinic receptors, specifically focusing on the role of a compound that Arthur received from Fred. Lastly, they discussed the progress of new drugs targeting specific receptors for various diseases, with Arthur sharing insights on Eli Lilly's compound, Xanomeline, and the potential of M4 PAM for psychosis. Collaborative Research and Translational Approach Arthur and Yamina from Monash University discussed their collaborative approach to scientific research, emphasizing the benefits of combining their complementary skills and interests. They shared their unconventional approaches to research, including the creation of a critical mass of GPCR researchers in Australia and the initiation of a successful series of conferences. They also discussed the relocation of some university labs to facilitate collaboration and overcome the siloed department structure. Additionally, they explored the unique culture and structure of their Institute, highlighting its translational approach to research and its capacity to translate research into therapeutic commercialization. Lastly, Arthur shared three significant moments that shaped his career, including the evolution and impact of analytical pharmacology, particularly highlighting the role of Prism, a data analysis tool. Podcast Format, Team Culture, and Science Yamina and Arthur concluded their discussion and decided to take a short break. They talked about the format and length of their podcast, their professional interests, and their recent successful bid to bring Moderna to their university. They also explored the idea of starting a similar talk show format to 'Between Two Ferns', the importance of maintaining team culture, and the potential health issues among well-known scientists. Lastly, they discussed the growth and development of the Monash Institute of Pharmaceutical Sciences, the importance of knowing when to let go in scientific experiments, and the idea of a panel for building and incubating companies. Arthur's Pandemic Journey and Global Challenges Yamina and Arthur discussed Arthur's experiences during the Covid-19 pandemic, his journey as a research fellow in Australia, and his transition to the role of Dean. Arthur shared his insights into the unique grant funding system in Australia, the importance of impact in research, and the challenges of balancing administrative responsibilities with scientific pursuits. He also reflected on his personal health struggles, the growth of his university, and the faculty's successful response to the Covid crisis. The conversation also touched upon Arthur's career decisions, his scientific achievements, and the importance of learning from mistakes and self-confidence. Lastly, they discussed the global challenges of healthcare workforce growth, climate change, and emerging psychiatric disorders, as well as the importance of recording lectures and having pre-lesson materials available to students. Translating Discovery Into Clinical Application Arthur and Yamina discussed the importance of translating fundamental discoveries into clinical applications in their research, highlighting the unique opportunities presented by their location and partnerships with other institutions. They stressed the necessity of making their research goals clearer, avoiding replication, and adopting a more assertive approach in grant applications. They also emphasized the significance of fundamental discoveries, the role of biotech, and the need for efficiency and process development in university systems. The conversation highlighted ongoing challenges within universities, including resistance to change and the need to communicate expectations and protect established cultures. Hiring Process, Collaboration, and Education-Focused Initiatives Arthur emphasized the importance of differentiation, impact, and interest in their hiring process and fostering a culture of collaboration. He shared his vision of breaking down barriers and promoting education-focused initiatives, encouraging his team to be innovative and apply their skills to education. Yamina expressed a desire to learn from successful leaders and the importance of recognizing talent and matching it with the needs of a particular project. They also discussed the disruption within the pharmaceutical sector, the importance of workforce development, and the need for maintaining a healthy work-life balance. Lastly, they deliberated on involving junior scientists and postdocs in their podcast and the possibility of writing a book about their experiences in academia. 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 >>

Stuart Maudsley on why receptor signaling shifts across a lifetime, and how high dimensional data turns biological complexity into therapeutic openings. << Back to podcast list Strategic Partner(s) Stuart Maudsley: Receptor Complexity, Aging, and the Limits of Single Target Drugs Scientific Abstract GPCR pharmacology has spent decades adding detail to a picture that keeps getting larger. Stuart Maudsley has worked at nearly every scale of that picture, from patch clamping neurokinin receptors as a graduate student to running high dimensional proteomic and informatic analyses of receptor systems across the lifespan. This conversation follows the idea that has shaped his work: a receptor is not a fixed object with a fixed output but a system that changes by the millisecond and by the decade. In that view, complexity is not an obstacle to therapy, it is the reason therapy is possible. Stuart Maudsley describes dimensional condensation, the practice of turning vast datasets into objects a person can look at and even hold, and the reasoning behind what he calls disease trajectory modifiers, compounds designed for people whose disease is still preclinical. Running underneath the science is a personal stake. He moved to the National Institute on Aging because his wife's grandfather was living with dementia, and the aging field became the frame for everything he has built since. About Stuart Maudsley Stuart Maudsley leads the Receptor Biology Lab at the University of Antwerp, where he is Vice Chair of the Department of Biomedical Sciences and Adjunct Director of the VIB Center for Molecular Neurology. He trained in pharmacology at the University of Leeds, then joined Robert Lefkowitz at Duke University on a Howard Hughes Medical Institute Fellowship before leading the Receptor Biology Section at the MRC Human Reproductive Sciences Unit in Edinburgh. He went on to head the Receptor Pharmacology Unit at the National Institute on Aging, based at the Johns Hopkins University Medical Center, where he received an NIH Bench to Bedside Translational Research Grant Award. His current work combines mass spectrometry, natural language processing and topological data analysis to build GPCR based therapeutics that act on the gerontological roots of disease, a research stream now forming the basis of the startup HeptOME. Scientific Themes of the Conversation Receptors as temporal systems: signaling that shifts across milliseconds and across a lifetime Low dimensionality versus high dimensionality biology, from one band on a western blot to eighteen thousand proteins on a mass spectrometer Dimensional condensation and topological data analysis as ways to make enormous datasets legible Polypharmacology and the case that complex systems respond only to complex inputs Aging framed as unrepaired damage, with disease as the visible end of a long silent process The culture of science: attrition, authorship order, and the loss of talented people the field cannot afford Key Insights from the Conversation Complexity supplies solutions, it does not remove them Most people treat biological complexity as a barrier to drug development. Stuart Maudsley argues the opposite, using type 2 diabetes as his example: because every patient's disease is molecularly distinct, the number of ways into the system is larger, not smaller. More dimensions of signaling means more places a therapeutic can enter. A receptor system cannot hold its shape for eighty years When he moved into aging research, one question reframed his entire field for him. What is the likelihood that a signaling system of this complexity is maintained with perfect fidelity across eight decades and every millisecond within them? The answer is zero, which means receptor pharmacology has to account for the age of the system it is acting on. Data becomes understandable when it becomes an object His lab condenses high dimensional datasets into three dimensional shapes and has 3D printed them so students can hold sixteen thousand data points in one hand. The logic borrows from convergent evolution: if a shark, a dolphin and an ichthyosaur converge on the same form under the same pressures, datasets under the same biological pressure may converge too. You cannot move a complex system with one finger Push a single finger into a jelly on a table and the finger sinks while the jelly stays put. Press with a whole hand and the jelly slides. It is his argument against monolithic single target drugs and for designing compounds that touch many nodes of a network at once, gently, relying on the system's own amplification. The body gets used to being ill Given long enough, a system drifting out of balance stops recognizing its healthy state as normal and becomes resistant to being returned to it. That reasoning leads to what he calls disease trajectory modifiers: acting during the preclinical phase, which upends the pharmacological convention of treating people only once they are unwell. Informatics is a difference engine, not an answer generator He is blunt with students who expect computational analysis to deliver truth. It tells you that two samples differ, not what is actually happening inside them. What he values instead is the zero hit PubMed search, the result with no precedent, where the finding arrives without his prejudice attached to it. Changing scientific language every five years has a cost he accepts A talk he wandered into at the NIH library on natural language processing rewrote how he analyzes biomedical data. He describes each such shift as adopting a new language, and is candid that the pattern is a career disadvantage: people are told to pick one thing and stay with it. He calls the reinvention painful and brutal, and does it anyway. Episode Timeline 00:00 Introduction 02:14 Star Wars, a BBC film about the discovery of DNA, and the choice of pharmacology 07:29 Writing to Robert Lefkowitz, and what a lab full of people talking in corridors actually taught him 20:10 Why pharmacology: a science that has to produce something 29:25 Natural language processing, and reading millions of papers without reading any of them 38:44 From low dimensionality to high dimensionality, and the eighteen thousand proteins behind every western blot 46:13 Dimensional condensation: turning datasets into objects students can hold 58:50 How aging entered the work, and why receptor systems cannot stay the same for a lifetime 01:16:58 The encrypton idea: how a cell decodes many ligands arriving at once 01:31:27 Drugs as software for a complex machine, and the jelly on the table 01:45:49 Disease trajectory modifiers: giving compounds to people who are not yet ill 02:29:13 Advice for young scientists: make the decision, then own it 03:18:29 Work, family, and the culture that keeps pushing women out of science Timestamps were generated using AI for readability. Selected Quotes "Talking beats working hard every day of the week, because you thrash out and you get the ideas and you write them on a board and things spark into your brain." "Every single year we realize there are a hundred more onion layers to go. It's never gonna stop." "A lot of people would see extra complexity as a problem. Actually what it means is more potential solutions, because not everyone will be disrupted in the same way." "My goal as a pharmacologist now is to give drugs to people that aren't unwell. That would be a crazy concept many years ago." Guest Links Maudsley Lab: https://www.uantwerpen.be/nl/personeel/stuart-maudsley/ LinkedIn: https://www.linkedin.com/in/stuart-maudsley-18a58328/ Google Scholar: https://scholar.google.com/citations?user=KQ6pwbEAAAAJ&hl=en&oi=ao ResearchGate: https://www.researchgate.net/profile/Stuart-Maudsley Maudsley Lab on Facebook: https://www.facebook.com/MaudsleyLab/ Receptor Biology Lab Facebook Group: https://www.facebook.com/groups/622756024785459 Twitter: https://twitter.com/StuartMaudsley Semantic Scholar: https://www.semanticscholar.org/author/Stuart-Maudsley/2308781 Instagram: https://www.instagram.com/receptorbiologylab/?hl=en Neurotree: https://neurotree.org/beta/peopleinfo.php?pid=780703 Dimensions: https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01133063535.04 Reddit: https://www.reddit.com/user/stuart-maudsley/ Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/search?q=Stuart+Maudsley 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. Joseph Kim exploring GPCR structural biology, cryo-electron microscopy, opioid receptor pharmacology, and the challenges of discovering ligands for understudied receptors like the galanin receptor family. << Back to podcast list Strategic Partner(s) Joseph Kim: Structural Biology and Drug Discovery at GPCRs Scientific Abstract G protein-coupled receptors (GPCRs) remain one of the most important classes of drug targets in modern pharmacology. In this conversation, Dr. Joseph Kim discusses the intersection of structural biology, membrane protein biochemistry, and drug discovery through the lens of GPCR research. Dr. Kim, a postdoctoral scholar in the laboratory of Dr. Aashish Manglik at the University of California, San Francisco, studies GPCR structure using cryo-electron microscopy. His work focuses on understanding how ligands interact with receptors such as the μ-opioid and κ-opioid receptors, and how structural insights can guide the development of new pharmacological modulators. The discussion explores how structural biology technologies—particularly cryo-EM—have transformed the ability to visualize receptor-ligand interactions and uncover the molecular mechanisms underlying receptor signaling. Dr. Kim also reflects on the conceptual challenges of studying membrane proteins, the value of pursuing difficult scientific problems, and how curiosity about drug mechanisms led him toward GPCR pharmacology. Listeners will gain insight into the scientific reasoning behind GPCR structural studies, the evolving toolkit used to interrogate receptor activation, and the broader landscape of receptor-based drug discovery. About the Guest Dr. Joseph Kim is a structural biologist studying membrane proteins and GPCR pharmacology. He is currently a postdoctoral scholar in the laboratory of Dr. Ashish Manglik at the University of California, San Francisco, where he uses cryo-electron microscopy to investigate ligand binding and receptor conformations. Dr. Kim’s research focuses on druggable membrane proteins, particularly GPCRs involved in neurological signaling such as opioid receptors and the galanin receptor family. His work combines structural biology, membrane protein biochemistry, and pharmacological insights to better understand how ligands modulate receptor signaling. His broader scientific interests lie at the interface of structural biology and drug discovery, where molecular structures inform the design and development of new therapeutics. Scientific Themes of the Conversation Structural biology of GPCR–ligand interactions Cryo-electron microscopy in membrane protein research GPCR pharmacology and drug discovery strategies Opioid receptor structure and ligand modulation Challenges in targeting peptide-binding GPCRs Exploring understudied receptors such as the galanin receptor family Key Insights from the Conversation 1. Difficult Scientific Problems Often Drive Discovery Dr. Kim describes a personal inclination toward challenging research areas. Membrane proteins—historically difficult to purify and structurally characterize—represent precisely the kind of problems that attract scientists interested in pushing methodological boundaries. 2. Structural Biology Reveals the Molecular Logic of Drug Action Through cryo-EM studies of the μ- and κ-opioid receptors, Dr. Kim explains how visualizing receptor-ligand complexes provides direct insight into how small molecules stabilize specific receptor states and produce pharmacological effects. 3. GPCR Drug Discovery Is Increasingly Structural Modern GPCR drug discovery increasingly integrates structural data, computational docking, and pharmacology. Structural snapshots of receptor-ligand complexes can validate docking predictions and guide medicinal chemistry. 4. Polypharmacology Is a Central Challenge One small molecule studied by Dr. Kim’s group interacts with multiple opioid receptors, acting as an antagonist at one receptor and an inverse agonist at another. This illustrates how receptor pharmacology often involves complex, receptor-specific effects. 5. Many GPCRs Remain Poorly Understood The galanin receptor family represents an example of GPCRs with important physiological roles but limited pharmacological tools. The lack of potent small-molecule ligands continues to hinder research into these receptors. 6. New Tools Enable Re-exploring Old Questions Advances in cryo-EM, computational modeling, and machine learning are enabling scientists to revisit receptors that were previously considered difficult to drug. 7. Scientific Environments Matter Dr. Kim emphasizes the importance of research environments that allow curiosity, experimentation, and even failure. Supportive collaborative environments accelerate scientific progress. Episode Timeline 00:00 — Introduction Introduction to Dr. Joseph Kim and his current position at UCSF. 01:00 — Early curiosity about drugs and poisons How childhood curiosity about toxic plants led to an interest in drug research. 05:00 — Choosing science over medicine Transition from a pre-medical track to pursuing scientific research. 07:00 — Discovering cryo-electron microscopy Graduate training in cryo-EM and early exposure to membrane protein structural biology. 10:00 — Pursuing challenging scientific problems Why difficult fields like membrane protein structural biology can be particularly appealing. 18:00 — Choosing a postdoctoral lab Criteria used to identify the right postdoctoral environment. 23:00 — The scientific appeal of membrane proteins How membrane proteins serve as the entry point for signaling molecules. 29:00 — Structural studies of opioid receptors Dr. Kim describes solving structures of μ- and κ-opioid receptors bound to small-molecule ligands. 34:00 — The galanin receptor: an understudied GPCR Why the galanin receptor family presents intriguing scientific questions. 45:00 — Scientific turning points Three key “aha moments” that shaped Dr. Kim’s scientific trajectory. 52:00 — Advice for young scientists The importance of curiosity, persistence, and choosing supportive research environments. Selected Quotes “The line between drugs and poisons is not so different.” “If someone tells me something is difficult, I tend to run toward it rather than away from it.” “Membrane proteins are where signaling begins—the moment a molecule tells the cell what to do.” “It’s perfectly fine to feel fear when entering a new field, but it shouldn’t stop you from pursuing the questions that excite you.” Full Transcript (Formatted for readability. Minor transcription artifacts removed while preserving scientific meaning.) Dr. Yamina Berchiche: Hello, everyone. This is Yamina from Dr. GPCR. I'm very excited to be recording this particular podcast episode. Joe reached out to me on LinkedIn, and we started a fantastic conversation, and I'm excited to bring you, Joe, to the podcast today. Joe Kim, welcome to the Dr. GPCR podcast. Dr. Joseph Kim: Thank you, Yamina. It's an absolute pleasure to be here. Dr. Yamina Berchiche: Very excited to have you on. Maybe we can start by you introducing yourself to the audience. Dr. Joseph Kim: My name is Joseph Kim. I go by Joe. I am currently a postdoctoral scholar in Professor Ashish Manglik’s lab here at the University of California, San Francisco. Dr. Yamina Berchiche: Wonderful. I’m going to put it out there on the record—I’ve been reaching out to Ashish. We're going to have to push him towards coming onto the podcast. I listened to one of his talks at a Gordon Conference and he was phenomenal. Ashish, if you’re listening to this—we want you on the podcast. So Joe, tell me a little bit about how you ended up working on GPCRs in Ashish’s lab. I’m really curious about your career trajectory. Dr. Joseph Kim: Sure. When it comes to how I got involved in GPCRs, I guess I can start from when I was a kid. I grew up in Corvallis, Oregon, which is a college town about 90 miles south of Portland. There were a lot of trees and outdoor flora and fauna around me. I spent a lot of time exploring and going to the library. One day I found a book about poisonous plants—essentially explaining which berries you could eat and which you absolutely shouldn’t. That’s probably where my interest in drugs and toxins began. There’s that saying that the difference between drugs and poisons is often just the dose. That fascination stuck with me. Later, during my final year of graduate school at UW–Madison, I was thinking about postdoctoral positions and reading papers about drug discovery. I remember distinctly sitting back one day and thinking: “Ah crud… I’m going to have to study GPCRs, aren’t I?” And that realization eventually led me to Ashish’s lab. Dr. Yamina Berchiche: How did you initially decide to pursue science? Dr. Joseph Kim: I was always interested in science growing up, especially health sciences. When I started college at Oregon State University, I entered as a pre-med student. But I realized something about myself—I would spend too much time asking why certain treatments were prescribed. That constant questioning felt more aligned with being a scientist than being a physician. Dr. Yamina Berchiche: You mentioned earlier that the project you worked on involved the μ-opioid receptor and the κ-opioid receptor with a small molecule that showed interesting pharmacology. What happened to that project? Was it eventually published? Dr. Joseph Kim: Yes, it was published this year in ACS Central Science . Dr. Yamina Berchiche: Congratulations—that’s wonderful. All right, I always ask this question from everyone who comes on the podcast. What is your favorite GPCR? Dr. Joseph Kim: People will probably assume that it’s one of the opioid receptors, but I’m actually going to surprise them. My favorite GPCR is not the opioid receptors. Instead, it’s the galanin receptor . Dr. Yamina Berchiche: The galanin receptor? I’m not very familiar with that one. Dr. Joseph Kim: Exactly—and that’s part of why I find it so fascinating. There are three members of the galanin receptor family: galanin receptor 1, 2, and 3. The one I’m most interested in is galanin receptor 1 . It’s highly expressed in the brain and spinal cord. There’s evidence suggesting that it plays roles in feeding behavior and analgesia , somewhat similar to opioid receptors. Some studies also suggest that the galanin receptors may interact with the μ-opioid receptor. In fact, some groups believe there may even be dimeric interactions between the receptors. But the major challenge is that no one has identified a potent small-molecule ligand for these receptors. Dr. Yamina Berchiche: That’s fascinating. Dr. Joseph Kim: Recently, structures of galanin receptors bound to their endogenous peptide ligand—galanin—were published. Those structures revealed something really unusual: the peptide binds laterally within the receptor. That unusual binding mode might explain why it has been so difficult to identify small-molecule ligands. Dr. Yamina Berchiche: That makes sense. Whenever I hear about peptide-binding GPCRs with buried or hydrophobic binding pockets, I immediately think: good luck finding small molecules. Dr. Joseph Kim: Exactly. The endogenous peptide is buried laterally within the receptor, which means an exogenous small molecule might have difficulty accessing that pocket. Dr. Yamina Berchiche: Unless you start thinking about allosteric modulators. Dr. Joseph Kim: Right—and once you start thinking about allosteric modulation, you open an entirely new set of questions. Dr. Yamina Berchiche: Absolutely. Especially when you consider that the galanin system involves three receptors and potentially different signaling pathways. I just looked it up while we were talking. It appears galanin has roles in nociception, depression, and sleep . That’s a complicated pharmacological landscape. Dr. Joseph Kim: It is. You could easily imagine separate therapeutic programs targeting those different physiological effects. And of course, that also means the pharmacology becomes much more complex. Dr. Yamina Berchiche: So how did you first encounter the galanin receptor? Dr. Joseph Kim: It actually came from discussions with Ashish when I first joined the lab. I told him I was interested in three things:• structural biology• drug discovery• neurological systems The galanin receptor fit all three of those interests. So Ashish introduced it as a potential project area, and it stuck with me. Dr. Yamina Berchiche: What kinds of questions are you hoping to answer about that receptor family? Dr. Joseph Kim: At a very basic level, one of the key questions is simply: Can we identify a small molecule that modulates the galanin receptor? In the early 2000s there were screening campaigns against these receptors, but nothing promising emerged. So the question becomes: Did we simply not search deeply enough?Or were the screening strategies themselves limited? With today’s tools—computational docking, structural biology, and machine learning—we might be able to revisit those questions in a more sophisticated way. Dr. Yamina Berchiche: I completely agree. We now have tools that simply didn’t exist ten or twenty years ago. That means receptors that were previously considered difficult or unproductive targets might be worth revisiting. But I also think we need to use these tools carefully. Dr. Joseph Kim: Yes, exactly. One of the risks with new technologies is that people sometimes build the research question around the tool rather than using the tool to answer the question. We need to integrate these tools thoughtfully rather than simply following the excitement. Dr. Yamina Berchiche: I agree. There are really two complementary directions in GPCR research. One direction is to develop new tools using well-characterized receptors—the ones we understand well enough to validate new methods. The other direction is to apply those tools to the more challenging or understudied receptors. Dr. Joseph Kim: Exactly. You need a solid foundation. If the receptor system and the tool are both unknowns, it becomes very difficult to interpret the results. Dr. Yamina Berchiche: That’s a great point. Let’s shift gears a little bit. Looking back at your career so far, what would you say are the three biggest “aha moments” that shaped your trajectory as a scientist? Dr. Joseph Kim: The first one was definitely the moment I described earlier—when I was sitting there reading papers and suddenly realized: “I’m going to have to study GPCRs.” That was a turning point. The second “aha moment” came when I solved the structures of the μ-opioid and κ-opioid receptors bound to the candidate small molecule we were studying. Showing those structures to my colleagues—and realizing that the experiment actually worked—was incredibly satisfying. It also helped me overcome the fear I had about transitioning into membrane protein structural biology. The third “aha moment” happened much earlier, when I switched from the pre-med track to pursuing graduate school. One of my close friends at the time noticed how quickly I pivoted once I realized that medicine wasn’t the right path for me. That moment clarified that research was the direction where I really belonged. Dr. Yamina Berchiche: That’s a beautiful chronological sequence. If we think about your future—have you started thinking about what comes after your postdoctoral work? Dr. Joseph Kim: Yes, I have. I would like to remain in drug discovery , ideally working on GPCRs if possible. I can imagine myself in a biotech or pharmaceutical environment where I’m helping guide drug development programs—evaluating data from different teams and deciding whether a candidate molecule should move forward. That might involve integrating information from pharmacology, toxicology, manufacturing, and preclinical research. Essentially serving as a bridge between the science and the development process. Dr. Yamina Berchiche: That sounds like an exciting direction. And finally, what advice would you give to young scientists who want to enter the GPCR field? Dr. Joseph Kim: The first piece of advice is don’t let fear stop you . It’s completely normal to feel intimidated when entering a complex field like GPCR biology. But that fear shouldn’t prevent you from pursuing ideas that excite you. The second piece of advice is to find an environment where you are allowed to learn from mistakes. The reason I was able to transition successfully into GPCR structural biology was because I joined a lab where people were supportive and willing to teach. Being in that kind of environment makes a huge difference. Dr. Yamina Berchiche: I completely agree. The worst thing you can do in science is nothing. Taking action—even if it leads to mistakes—helps you learn and move forward. Joe, thank you so much for joining the podcast today. I really enjoyed our conversation. Dr. Joseph Kim: Thank you, Yamina. It’s been an absolute pleasure. Dr. Yamina Berchiche: Thank you. 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. Daniel Wacker About Dr. Daniel Wacker I obtained my B.Sc. degree from the University of Munich performing work in the lab of Dr. Roland Beckmann with a brief stay at Cambridge University, UK, working in the lab of the late Dr. Kiyoshi Nagai . I then obtained an M.Sc. at the University in Munich working e.g. in the lab of Patrick Cramer . I next moved to Rockefeller University in NYC to work in the lab of the late Dr. Guenter Blobel , before starting my Ph.D. in 2009 at The Scripps Research Institute in La Jolla. There I obtained my Ph.D. in the lab of Dr. Ray Stevens in 2013 solving several GPCR crystal structures, including that of the first serotonin receptor. I then moved to UNC at Chapel Hill to do postdoctoral work in the lab of Dr. Bryan Roth where I established GPCR structural biology and learned the ins and outs of molecular pharmacology and in vitro drug discovery. In 2018 I started my own lab at the Icahn School of Medicine at Mount Sinai in NYC, where I have been working on structure-function and drug discovery of GPCRs and transporters. Dr. Daniel Wacker on the web Website LinkedIn Twitter 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 >>

Live webinar with Dr. Terry Kenakin on tuning GPCR system sensitivity to reveal true drug activity. September 24, 2026. Free. < Back to Webinars 📅 Thursday, September 24, 2026 at 11:00:00 AM EDT 🤝 Webinar in collaboration with: Eurofins DiscoverX Tuning GPCR System Sensitivity: Revealing True Drug Activity Through Functional Volume Control Dr. Terry Kenakin shows how tuning receptor expression separates affinity from efficacy, unmasks hidden agonism and inverse agonism, and helps predict how a compound will behave in vivo. The pharmacology of a drug is shaped not only by the molecule but by the sensitivity of the system it is measured in. Receptor density and coupling efficiency change what a ligand appears to do, which is part of why in vitro results do not always translate in vivo . This session presents functional volume control, the deliberate tuning of system sensitivity, as a way to separate a ligand's true affinity and efficacy from the system it was tested in. Dr. Terry Kenakin will show how reducing sensitivity lets you measure affinity and relative efficacy and turn low-efficacy agonists into measurable antagonists, how increasing sensitivity uncovers efficacy hidden in apparently neutral compounds, and how greatly increasing it reveals inverse agonism through constitutive activity. The same approach distinguishes what an allosteric modulator does to affinity versus efficacy, including PAM-agonism. Examples run across inducible, low, and medium expression systems. Why System Sensitivity Changes What You Measure The response to an agonist depends on its concentration and efficacy, and on the system: how many receptors are present and how well they couple to their effectors. Two assays with different sensitivities can report different behavior for the same molecule. Treated as a variable to control for, that is noise. Set on purpose, it becomes a measurement tool. From the Assay to the Candidate Reduce sensitivity and affinity separates from efficacy, so system-independent values can be measured and used to predict behavior elsewhere. Raise it and low-level efficacy that would drive agonism in a sensitive tissue becomes visible. Raise it further and inverse agonism appears where a calcium assay would have called the compound a neutral antagonist. Each setting answers a different question about a real candidate. Speaker Dr. Terry Kenakin Professor of Pharmacology and Pharmacology Course Coordinator Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill Head Instructor, Terry's Pharmacology Corner Dr. Kenakin trained in chemistry and pharmacology at the University of Alberta and completed postdoctoral work at University College London in the laboratory of Sir James Black. He spent 25 years in drug discovery at Glaxo, now GlaxoSmithKline, before joining UNC Chapel Hill, where he teaches and leads research in receptor pharmacology. His work is central to the quantitative framework used today to describe receptor signaling bias, allosteric function, and agonism. He proposed one of the first mechanistic explanations of biased signaling and co-authored the widely applied simple method for quantifying functional selectivity. He is the author of A Pharmacology Primer, Editor-in-Chief of the Journal of Receptors and Signal Transduction, and a Fellow of the British Pharmacological Society, recognized with the Goodman and Gilman Award from ASPET and the Gaddum Memorial Award. Within the Dr. GPCR ecosystem, he is Head Instructor of Terry's Corner, a space for live AMAs, short-form mechanistic discussions, and ongoing dialogue with the GPCR community on receptor theory, biased signaling, and the decisions that shape real drug discovery programs. Organizers Eurofins DiscoverX Eurofins DiscoverX is a one-stop-shop for GPCR drug discovery and development, with 25+ years of expertise and validated cell-based assays spanning basic research through therapeutic discovery, optimization, and regulatory submission. Their assays are industry-standard, accepted for regulatory potency testing, and backed by thousands of peer-reviewed publications and partnerships with leading pharma and biotech companies. >1,500 human GPCR products covering ~90% of the GPCR-ome, including orphan receptors and ortholog variants Multiple mechanisms of action: cAMP accumulation, β-arrestin recruitment, receptor internalization, ligand binding, calcium flux, pharmaco-chaperone discovery Flexible formats: cell line assay kits, ready-to-use eXpress kits, qualified bioassays, membrane preps, detection kits, and custom products Applications across target identification, HTS, lead optimization, ligand bias and allostery evaluation, safety assessment, and regulatory potency testing Dedicated portfolio for obesity and diabetes GPCR targets (GLP-1R, GIPR, GCGR, MC4R, AMY receptors, and more) Dr. GPCR Dr. GPCR is a membership-based nonprofit ecosystem dedicated to advancing GPCR-targeted drug discovery. It provides curated industry intelligence, expert-led masterclasses, and structured engagement opportunities for scientists and biotech leaders working across pharmacology, translational research, and therapeutic development. Curated intelligence on GPCR drug discovery trends and developments Expert-led webinars and masterclasses with leading researchers Structured networking for scientists and biotech professionals Nonprofit model, community-first, member-driven Free membership tier available Previous Webinar Next Webinar Don’t Miss the Next Live Session Dr. GPCR membership gives you access to all upcoming live, interactive webinars. Free. Takes less than a minute to join. Cancel anytime. Sign Up for Free

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

<< Back to podcast list Strategic Partner(s) Tanishka S. Saraf About Tanishka S. Saraf " My research focuses on evaluating and targeting serotonin 1A receptors for therapeutic outcomes for Fragile X Syndrome. During my PhD, I learnt radioligand binding assays, behavioral assays, autoradiography, stereotaxic surgeries, electroencephalography, immunohistochemistry, mouse colony management and breeding. I would like to keep working in the central nervous system disorders realm to understand the neurobiology of neuropsychiatric disorders and to develop safe and effective treatments. " Tanishka S. Saraf on the web FRAXA Research Foundation Google Scholar ResearchGate LinkedIn Dr. GPCR Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Alix A. J. Rouault About Dr. Alix A. J. Rouault "My contribution to science began during the equivalent of U.S. masters training at the Université de Bretagne Occidentale (UBO; France). Under the leadership of Dr. Karine Pichavant , I contributed to the development of a drug to treat hypovolemic shock after severe hemorrhage. During this time, Dr. Olivier Mignen , the director of another research unit at the UBO recommended me to Dr. Julien Sebag , a researcher at the University of Iowa. I spent two years working with Dr. Sebag as an exchanged scholar while my student visa was in the work, during which time I thoroughly reviewed the literature on the melanocortin receptor accessory protein 2 (MRAP2), resulting in my first peer-reviewed publication in Biochimica et Biophysica Acta (BBA). I then undertook my first project where I demonstrated that MRAP2 regulates the signaling of multiple G protein-coupled receptors (GPCRs) through different structural regions. This project yielded my first, first author publication in BBA – Molecular Cell Research, and a book chapter for Neuromethods on a technique I adapted to measure the mitochondrial pyruvate oxidation in primary neurons. In 2017 I officially joined the PhD program in the Department of Molecular Physiology and Biophysics at the University of Iowa Carver College of Medicine, under the mentorship of Dr. Sebag. During my PhD, I continued my studies on MRAP2. I contributed to an In-vivo project that showed that MRAP2 regulates the growth hormone secretagogue receptor-1a (GHSR1a), the results of which are published in Nature Communications. Concurrently, I described the mechanisms by which MRAP2 regulates GHSR1a signaling; this project brought forth our NanoBiT-based arrestin recruitment assay. At the time, NanoBiT was a prototype technology we gained access to by collaborating with Promega. This powerful tool allowed us to create an assay that kinetically measured the arrestin recruitment to an activated GPCR for the first time. Using this novel technique, I showed that MRAP2 biased GHSR1a signaling and shut down its constitutive activity; this work resulted in a first author publication in Science Signaling. While writing my thesis, I published another paper in the Journal of Biological Chemistry which described the molecular mechanisms of MRAP2 regulation of the GHSR1a, and where I notably developed the C-terminal gate theory. This theory states that the post-translational modification of GHSR1a’ C-terminal tail is not a docking space for the arrestins, but rather a necessary modification leading to a structural change granting the arrestins access to the core of the receptor. Some of my data were also used in an In-vivo study published in iScience, showing the relevance of the MRAP2 regulatory effect on GHSR1a in pancreatic islets. Dr. Cone’s lab was a clear choice for a postdoc. Dr. Cone was the first to clone the melanocortin receptors (the GPCRs that led to the discovery of MRAP2), and his lab works is highly In-vivo oriented. Since I joined the lab, I became proficient in many In-vivo techniques, I adapted my arrestin recruitment assay to a high throughput screening format for drug discovery, I have started molecular work on the melanocortin receptors. I also invested a tremendous amount of time in developing my leadership skills. I spent time running for the chair of International Affairs for the U-M Postdoctoral Association (UMPDA). Further, I applied to create a scientific session at the American Physiology Summit (APS) 2024 dedicated to GPCR biased signaling. Dr. Lauren Slosky and Dr. Joshua Gross were enthusiastic about the idea and jumped on board. Our session was picked up by the APS. We were pleasantly surprised by the interest generated by our scientific session, Dr. Michel Bouvier accepted to open our session and will be followed by Dr. John McCorvy , Dr. Dylan Eiger , and Joshua Gross. We are very excited about this event. At this point in my career, I am creating connections with biomedical industry, assessing professional opportunities, and seriously weighing strengths of career options across sectors; however, academia does not make information about industry widely accessible to trainees. This is, in part, why I ran for, and was elected Chair of International Affairs of the University of Michigan Postdoc Association. I want to connect more trainees with diverse career resources to support professional decision-making. I am hopeful that my efforts to support the professional opportunities of my peers, in combination with my own scientific endeavors, will inform my future career decisions." Dr. Alix A. J. Rouault on the web University of Michigan Carver College of Medicine ResearchGate Google Scholar 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 >>

GPCR pharmacologist Dr. Arun Shukla on how two beta-arrestin isoforms regulate over 800 receptors, why "non-canonical" GPCRs are nature's own biased receptors, and building a structural pharmacology lab in India. << Back to podcast list Strategic Partner(s) Arun Shukla: How Two Arrestins Regulate 800 GPCRs The human genome encodes more than 800 GPCRs — and just two beta-arrestin isoforms to regulate their signaling, endocytosis, and degradation. How two structurally similar proteins orchestrate such functional diversity across an entire receptor superfamily remains one of pharmacology's most stubborn unsolved problems. Dr. Arun Shukla's lab at the Indian Institute of Technology, Kanpur attacks this question from multiple angles: structural snapshots by cryo-EM and crystallography, dynamic information from NMR and hydrogen-deuterium exchange, and custom-engineered antibody fragments that both stabilize transient complexes and report on their conformations in live cells. His team also works on so-called non-canonical GPCRs — receptors once dismissed as non-functional because they don't couple to G proteins — and has helped establish that these are, in effect, nature's own beta-arrestin-biased receptors. For Dr. Shukla, the question of how two proteins manage 800 others isn't abstract — it's the one that pulled him back from Lefkowitz's lab at Duke to build a structural pharmacology program from the ground up in India. About the Guest Dr. Arun Shukla leads a structural pharmacology lab in the Department of Biological Sciences and Bioengineering at the Indian Institute of Technology, Kanpur. His research focuses on the structural and functional basis of GPCR–beta-arrestin interactions, combining cryo-electron microscopy, X-ray crystallography, NMR, hydrogen-deuterium exchange, and engineered antibody fragments to resolve how beta-arrestins recognize and regulate a diverse receptor family. He completed his PhD at the Max Planck Institute of Biophysics in Frankfurt and postdoctoral training in Bob Lefkowitz's lab at Duke University before returning to India in 2014. Among his lab's contributions are antibody-based intrabodies that inhibit receptor endocytosis in live cells and biosensors that visualize beta-arrestin conformations across multiple receptor systems. Scientific Themes of the Conversation The structural and functional basis of GPCR–beta-arrestin coupling How two beta-arrestin isoforms regulate an 800-member receptor family Non-canonical GPCRs as physiological beta-arrestin-biased receptors Engineered antibody fragments as tools for structural stabilization and live-cell conformational reporting The limits and promise of biased agonism in drug discovery Methodological triangulation — pairing static structures with dynamic measurements and cellular validation Key Insights from the Conversation Two proteins, eight hundred receptors The central puzzle driving Dr. Shukla's lab is also one of the field's oldest open questions: how do just two beta-arrestin isoforms, structurally nearly identical, mediate the signaling, endocytosis, and ubiquitination of over 800 distinct GPCRs? The answer lies somewhere in the diversity of receptor architectures — long C-termini versus long ICL3s, phosphorylation patterns, and a conformational flexibility arrestins must dynamically adapt to. The "non-functional" GPCRs were never non-functional Receptors like CXCR7, C5L2, and TQIP6 were long dismissed as non-canonical because they don't couple to G proteins. Dr. Shukla's lab and others have shown they signal robustly through beta-arrestins — which makes them, in effect, physiological examples of the beta-arrestin-biased receptors pharmacologists have been trying to design from scratch. Biased agonism is harder than the opioid story suggested The neat bifurcation between G-protein and beta-arrestin signaling that drove early opioid receptor drug design has not held up cleanly in subsequent studies. Cell context, assay choice, and receptor conformational heterogeneity all contribute to outcomes. The concept remains powerful, but it demands better tools and more careful interpretation than the field initially assumed. An antibody built for one job that did another Dr. Shukla's lab designed antibody fragments to stabilize GPCR–beta-arrestin complexes for structural studies. One of them did the opposite: it disrupted the beta-arrestin–clathrin interaction and became a generic inhibitor of receptor endocytosis. The team kept it. That moment of unplanned utility is a recurring theme in his lab. One biosensor, conserved structure and hidden diversity An intrabody raised against the active conformation of beta-arrestin-1 bound to the vasopressin receptor tail was expected to be receptor-specific. It wasn't. It recognized beta-arrestin-1 complexes for the neurotensin and complement C5a receptors — but not every GPCR. That selective cross-reactivity turned the reagent into a visual probe of which receptor-arrestin pairs share a conformational fingerprint and which don't. The moment research stopped being a question During his master's at JNU, Dr. Shukla wasn't sure research would be his career. Then he started his thesis project and found himself skipping theory classes to be in the lab. That's when the question answered itself. For many scientists, the origin moment is this ordinary and this decisive. What a one-line email to Bob Lefkowitz can do Toward the end of his PhD in Frankfurt, Dr. Shukla wrote to Bob Lefkowitz at Duke — no formal interview, no rotation, just a CV and a short note. Lefkowitz invited him. It's a small correction to the assumption that elite postdocs require elaborate application rituals. Episode Timeline 00:00 Introduction 02:15 From DNA quadruplexes to GPCR structural biology 06:32 The master's project that made research a career 08:35 The puzzle — two arrestins, 800 GPCRs 14:29 Antibody fragments, intrabodies, and biosensors 21:09 Non-canonical GPCRs as nature's own biased receptors 23:43 When biased agonism got complicated 38:55 The intrabody they didn't mean to make 43:36 Building a more diverse GPCR community 49:47 Running a lab in India through the pandemic Timestamps were generated using AI for readability. Selected Quotes "There are more than 800 GPCRs, as you know, but there are only two isoforms of beta-arrestins. They're structurally very similar, but they can have quite a significant degree of functional divergence. The key question that continues to fascinate us is how two isoforms of beta-arrestins are able to interact with such a large repertoire of GPCRs and regulate their function." "I was not, to be honest, sure if research was what I wanted to take up as a career. But once I started working in a research lab for my master's thesis, I loved it so much that I would miss my theory classes to work in the lab. That is where I realized research is what I want to do for the rest of my life." "One name that kept popping up was Bob Lefkowitz. I wrote an email to him. No formal interview, nothing of that sort. I just shared my CV, and he invited me." "Initially we thought — I personally thought — that this is not what we want. But then later we realized in the lab that even if it is not what we want, it can be used for other things." About this episode In this episode of the Dr.GPCR podcast , my guest is Dr. Arun Shukla from the Indian Institute of Technology in Kanpur, India. Arun is currently an Associate Professor & Joy Gill Chair Professor, Intermediate Fellow, Wellcome Trust DBT India Alliance Swarnajayanti Fellow & EMBO Young Investigator at the Department of Biological Sciences and Bioengineering. He earned his master's degree in biotechnology from Jawaharlal Nehru University in India and it was during a biochemistry class where he learned about cell signaling that he became curious and wanted to learn more about it. Arun first started working on GPCRs and their structural characterization at the Max Planck Institute of Biophysics where he completed his doctoral studies in the lab of Dr. Hartmut Michel . Fascinated by GPCRs he wrote to Dr. Bob Lefkowitz and asked him if he could join his lab at Duke University. Dr. Shukla spent several years in the Lefkowitz lab and collaborated extensively with Dr. Brian Kolbika of Stanford University. Join us and learn more about Dr. Shukla’s research and how working in the lab instead of going to classes made him realize that research is what he wants to do for the rest of his life. Dr. Arun Shukla on the web Indian Institute of Technology Dr. Arun Shukla Lab Google Scholar PubMed Wikipedia LinkedIn 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. Christel Menet About Dr. Christel Menet "I did my Ph.D. in Manchester UK with Prof Jonathan Clayden in organic chemistry. I then started my career at Evotec before moving to Domain Therapeutics (called Faust pharmaceutical at the time). After 2 years, I joined Galapagos where I spent almost 11 years and became head of medicinal chemistry. 6 years ago I decided to take on a new challenge by taking the position of CSO at Confo Therapeutics . I was the 6th employee and today we are more than 60 :) I have fun every day, and I love working with GPCRs. they are such great targets." Dr. Christel Menet on the web Hyphen Projects GPCRS Drug Discovery Confo Therapeutics LinkedIn Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

<< Back to podcast list Strategic Partner(s) Dr. Stuart Maudsley About Dr. Stuart Maudsley Stuart graduated from the University of Leeds in the U.K. with a First Class Honors degree in Pharmacology. At the end of his studies, he was awarded the Pfizer Prize for undergraduate research. He then completed his Ph.D. at Leeds as well as the University’s Ackroyd, Brotherton, and Brown Scholar. Following his Ph.D., Dr. Maudsley was awarded a Howard Hughes Medical Institute Fellowship to train with Professor Robert Lefkowitz at Duke University. Following this tremendous experience, he was recruited to be the Principal Investigator of the Receptor Biology Section at the Medical Research Council (MRC) -Human Reproductive Sciences Unit within the University of Edinburgh. At the MRC he developed novel prostate cancer therapeutics based upon his research into GPCR pluridimensional signaling. To broaden his biomedical skill-set Stuart next accepted the position of Head of the Receptor Pharmacology Unit at the National Institutes of Health – National Institute on Aging at the Johns Hopkins University Medical Center. At the NIH he was the recipient of the coveted NIH ‘Bench-to-Bedside’ Translational Research Grant Award, one of the few awards available within the intramural NIH program. Upon starting a new family, and returning to Europe, Dr. Maudsley continued his scientific journey with the award of the highly-valued Odysseus Program Type I Program Grant to work as both the Adjunct Director of the VIB Center for Molecular Neurology and also Vice-Chair of the Department of Biomedical Sciences at the University of Antwerp. Stuart’s current research, in the Receptor Biology Lab, focuses on the development of novel GPCR-based therapeutics that interdict diseases based on their gerontological underpinnings. This research stream is now forming the basis of a new technology-based start-up company, HeptOME , to help screen and develop novel longevity/disease-regulating compounds with multidimensional disease efficacy profiles. Dr. Stuart Maudsley on the web Maudsley Lab LinkedIn Google Scholar ResearchGate Maudsley Lab on Facebook Receptor Biology Lab Facebook Group Twitter Semantic Scholar Instagram Neurotree Dimensions Reddit Dr. GPCR Ecosystem Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

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

Dr. John Streicher on how HSP90 flips direction between brain and spinal cord, why isoform-selective inhibitors may rescue oral delivery of opioid adjuncts, and how a student's side project on intermittent fasting erased morphine reward in mice. << Back to podcast list Strategic Partner(s) Dr. John Streicher: Reorganizing Opioid Signaling Beyond the Receptor The dominant strategy for improving opioid therapy has been to engineer new ligands at the receptor itself — biased agonists, partial agonists, multi-target molecules. Dr. John Streicher's laboratory at the University of Arizona works a different angle. His team treats opioid signaling as a problem of circuit organization: the same kinases and second messengers produce radically different outcomes depending on how they are scaffolded inside a cell, and the chaperones that do that scaffolding are themselves druggable. In this conversation, Dr. Streicher describes how heat shock protein 90 plays directly opposite roles in the brain and the spinal cord, why isoform-selective HSP90 inhibitors may finally solve the "brain always wins" problem of oral delivery, and how a graduate student's skeptically-received side project on intermittent fasting produced some of the strongest opioid-sparing data his lab has generated. He came to this field because a signaling cascade felt like a puzzle he could not stop thinking about, and the puzzle has only gotten more interesting. Listeners will get a concrete look at what it means to modulate opioid pharmacology downstream of the receptor — and why the safety margins the field has been chasing for decades might actually live there. About the Guest Dr. John Streicher is an assistant professor in the Department of Pharmacology at the University of Arizona. His lab combines cell and molecular biology with animal pharmacology to identify new signaling regulators of the mu, delta, and kappa opioid receptors. Current lines of work include isoform-selective HSP90 inhibition as a strategy for widening the opioid therapeutic index, signal organization downstream of opioid receptors, and the unexpected effects of intermittent fasting on morphine pharmacology. Dr. Streicher trained in signal transduction during his PhD on heart failure and p38 MAP kinase, and moved into opioid pharmacology as a postdoctoral fellow with Dr. Laura Bohn at Scripps Research Institute. Scientific Themes of the Conversation Opioid signaling specificity as a problem of circuit organization, not molecular identity HSP90 as a region-specific signaling scaffold — opposite roles in brain and spinal cord Isoform-selective chaperone inhibition as an alternative to receptor-level drug design The current state and replication troubles of biased agonism at the mu opioid receptor Downstream pharmacology as an underexplored route to safer opioid therapy Intermittent fasting as a metabolic modulator of opioid antinociception and reward Key Insights from the Conversation Specificity lives in circuit architecture, not in the kinase itself. ERK MAP kinase is Dr. Streicher's recurring example: the same molecule promotes opioid antinociception in one context, drives chronic pain in another, and functions as a mitogen in cancer. You cannot explain specificity by assuming each node does one thing. What differs is how scaffold proteins localize the kinase into distinct submolecular circuits. He teaches his students to think of kinases as components — a diode in a radio and a diode in a nuclear bomb can be identical — and the organization around them decides the outcome. HSP90 runs opposite programs in brain and spinal cord. In the brain, HSP90 promotes ERK activation downstream of the mu opioid receptor and is required for antinociception. In the spinal cord, the same chaperone acts as a brake on ERK activation. Block it spinally and the dorsal horn lights up with phospho-ERK in response to opioid, routing through RSK1/2 to stronger pain relief. Block it in the brain and antinociception collapses. This is not a quirk — it is the central clue the lab has built a therapeutic strategy around. The "brain always wins" problem is solved by isoform selectivity, not by dose. With a non-selective HSP90 inhibitor given systemically, the brain effect dominates and pain relief is lost. But the brain only uses HSP90α in this context, while the spinal cord recruits α, β, and GRP94. Collaboration with Dr. Brian Blagg at Notre Dame on β-and-GRP94-selective compounds has produced proof-of-concept IV data that reproduces the spinal-cord benefits — more potent morphine, reduced tolerance — without the brain blockade. The route from "intrathecal only" to "oral pill" runs through isoform selectivity. Biased agonism is in a harder place than the field often acknowledges. TRV-130 was denied FDA approval for lack of clear safety advantage. A phospho-null mu knock-in mouse from Stephan Schulz's group showed reduced tolerance but no respiratory-depression benefit. Attempts to replicate the arrestin-knockout phenotypes on clean mouse backgrounds have failed. Dr. Mary Canals' group has argued that some of the apparent bias benefits may actually reflect low intrinsic efficacy. Dr. Streicher calls himself an "informed outsider" on bias now, but his read is that the field needs deeper mechanism before the strategy can be rescued. A student's side project erased morphine reward. Graduate student David Duran wanted to test intermittent fasting in mice. Dr. Streicher was skeptical but gave the project room. The result: a six-hour feeding window for seven days increased morphine's antinociceptive efficacy in multiple pain models, strongly reduced tolerance and constipation, and completely blocked morphine reward in conditioned place preference. Receptor signaling assays showed efficacy shifts in the spinal cord and tolerance attenuation in the periaqueductal gray. The paper is published in Pain , and the translational path is unusually short — you don't need a ten-year IND process to test a feeding schedule in patients. Do not pursue something "completely novel" as a junior scientist. HSP90 in opioids was far enough off the beaten path that Dr. Streicher spent years fielding reviewer skepticism — no one has studied this, is this even real? His retrospective advice is to pick something novel but "still in the tent" — close enough to what the field recognizes that you earn credibility before trying to chase the real heresies. The lesson is not to play it safe; it is that unfamiliarity costs you credibility before your data can speak. Broad targets are not automatically undruggable. HSP90 is 2–3% of the protein content of every eukaryotic cell. A trained pharmacologist's first instinct is that the side effect burden would be crushing. But second-generation pan-HSP90 inhibitors have shown acceptable tolerability in oncology trials, Dr. Brian Blagg's KU-32 actually promotes neuronal survival in diabetic peripheral neuropathy and is now in Phase 1, and isoform selectivity narrows the footprint further. Dr. Streicher argues the field's default assumption — pick a low-expression, tissue-restricted target — is more habit than rule. Episode Timeline Timestamps were generated using AI for readability. 00:00 Introduction 01:22 Meet Dr. John Streicher 01:49 From heart failure to opioids — a path through signaling 07:49 Why the mu receptor still anchors his lab 09:51 The specificity puzzle — why ERK does a million things 13:31 What happened to biased agonism — replications in trouble 19:08 What's missing, and why HSP90 flips in the spinal cord 28:44 The "brain always wins" problem and isoform selectivity 33:05 HSP90 as Pac-Man — co-chaperones and the AHA1 clue 38:52 Picking projects that are "novel but in the tent" 47:25 The student's side project that blocked morphine reward 59:52 Running a lab through the first months of COVID Selected Quotes "A diode in your radio at home and a diode in a nuclear bomb could be exactly the same component but do radically different things depending on how they're organized." "The brain always wins. And when the brain wins, the antinociception is blocked — which is not what you want." "I'm normally a pretty skeptical, hard-headed person. But the data is the data. And I'm going to follow it." "Pick something that is novel, but is sort of still in the tent." About this episode Our guest in this episode of the Dr.GPCR podcast is Dr. John Streicher from the department of pharmacology at the University of Arizona. John started grad school in 1999 and spent some time figuring out what he was interested in. It turns out that it was signal transduction, and he worked on the signaling cascades involved in heart failure. His encounter and interest in signaling in the context of GPCRs during his postdoctoral training in Dr. Laura Bohn’s lab at Scripps Research Institute in Florida. Today, John and his team focus on understanding how signal transduction cascades downstream of the opioid receptors work, including the unique organization of chaperone protein Hsp90 modulation of opioid signaling in the brain versus the spinal cord. Dr. John Streicher on the web University of Arizona Department of Pharmacology Google Scholar Pubmed 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. Alex Serafini shares why pain research must start with real-world behavior and models before drilling into GPCR targets — a top-down rethink for drug discovery. << Back to podcast list Strategic Partner(s) GPCRs and the Science Behind Pain and Recovery with Dr. Alex Serafini Strategy: From Personal Pain to Scientific Purpose Dr. Alex Serafini’s entry into science wasn’t typical. Born in California, raised in Silicon Valley, and initially eyeing finance, his trajectory took a sharp turn after struggling with unresolved, chronic pain following repeated surgeries for a pilonidal cyst. "I wasn't able to get stronger pain meds because of the opioid epidemic," he recalls. That gap in care sparked a curiosity that became a career. Driven by personal experience and a desire to innovate in pain management, Alex pursued a master's in pain research at Hopkins and later an MD-PhD at Mount Sinai. His early exposure to TRPV1 channels and peripheral pain mechanisms with Dr. Mike Caterina laid the foundation. But the deeper mission? Finding answers for patients society often overlooks. Pain became more than biology — it became a personal strategy. “I started going through what I was going through… and that got me very interested in research.” — Alex Serafini Decision-Making: Saying Yes to the Unorthodox Path Serafini’s journey defied traditional checklists. He joined Mount Sinai through FlexMed — bypassing the MCAT — and was torn between a career in pharma and academia. At one point, he had a job offer at Roivant (a biotech firm known for repurposing shelved compounds), but a late-stage offer into an MD-PhD program — and parental “encouragement” — rerouted his path. His approach to decision-making is pragmatic: follow impact, not orthodoxy. The decision to stay on as a postdoc in the same lab as his PhD — with Dr. Venetia Zachariou — wasn't the typical next step, but it allowed him to wrap up high-impact work and learn about PI-level grant writing, strategy, and lab management. In his words: “She let me run projects like a junior PI.” “I didn’t need to chase new techniques — I needed to finish the science that mattered.” — Alex Serafini Blind Spots: The Underestimated Role of RGS Proteins in Pain Although not a self-proclaimed GPCR specialist, Serafini found himself repeatedly drawn to them, or more precisely, to RGS (Regulators of G protein Signaling) proteins. The lab’s work with RGS4 led to unexpected results: knockout mice spontaneously recovered from chronic pain after three weeks, an effect rarely observed. He points out that GPCRs—especially orphan and CNS-associated ones—are often downplayed in pain research, with most focus on ionotropic targets like NAV1.8. But Serafini believes that’s a blind spot. “We’re using outdated drugs. There are more elegant GPCR targets waiting to be explored.” The lab’s unconventional in vivo-first strategies, combined with RNA-seq and behavioral analysis, revealed nuanced roles of RGS4, RGS9, and RGSZ — not just as modulators but as potential therapeutic linchpins. “Half the time, in pain, what works in vivo doesn’t translate to clinic. We need new thinking.” — Alex Serafini Failure & Frustration: From Pipettes to Pandemic Disruption The road hasn’t been smooth. From struggling to grip mice in early animal studies to thesis delays during COVID-19, Serafini's journey is marked by grit. But it’s in these friction points that new insights emerged. The pandemic disruption, for instance, led him to BSL-3 labs to study persistent pain after SARS-CoV-2 infection, revealing novel immune-neuron signaling in DRGs. He also opens up about the emotional and logistical toll of MD-PhD training. It’s an eight-year-plus haul with built-in uncertainty. However, with mentors who believed in him, especially those who shared administrative, grant-writing, and leadership skills early on, he found direction and resilience. “She [Vanna] gave me a crash course in what it’s like to be a junior PI. That changed everything.” — Alex Serafini Pivoting: Redefining the Pain Research Playbook Looking ahead, Serafini’s vision is bold: build a lab that develops translational models of pain rooted in patient realities. He’s fascinated by transgenerational epigenetics — how parental pain, diet, or drug exposure can leave molecular fingerprints in offspring. He's equally focused on sex differences in pain processing and the failure of "one-size-fits-all" models in pharmacology. His advice? Learn broadly. Stay close to patients. Collaborate relentlessly. And above all, don’t be afraid to start from the phenotype and work backwards to the mechanism. That top-down approach, though less common, could help pain research finally catch up with the complexity of real-world biology. “Start from the end — from the clinic — and then build backwards.” — Alex Serafini Key Takeaway Innovation in pain research won’t come from doing the same things better — it’ll come from flipping the script. Whether it’s challenging legacy targets, redefining preclinical models, or exploring the epigenetic inheritance of pain, Dr. Serafini urges the field to stay bold, patient-centered, and GPCR-aware. About Alex Serafini Alex was born and raised in the Bay Area and received his BS/MS Neuroscience from Johns Hopkins. His master's degree was in Dr. Michael Caterina's lab studying the role of PNS chloride transporters in neuropathic pain. Upon matriculating to Mount Sinai's MD/PhD program, he joined Dr. Venetia Zachariou's lab to study the effects of chronic pain and addiction/withdrawal on the mesocorticolimbic system, focusing on transcription factor and RGS protein maladaptations, behavioral RGS protein drug "screening", and the role of SARS-CoV-2 on CNS function and sensory hypersensitivity. He aspires to become a physician-scientist, with a focus on translational in vitro and in vivo model development for studying chronic pain and affective comorbidities. Other academic interests of his include studying pharmaceutical finance & healthcare administration and developing technologies that increase healthcare access. His non-academic interests include traveling, scouting out micro-breweries, and collecting beer cans. Alex Serafini on the web LinkedIn Unlock the Full Dr. GPCR Learning Ecosystem ✔ Full Masterclass library ✔ Terry's Pharmacology Corner ✔ Advanced GPCR courses ✔ Scientific discussions → Become Premium Upcoming Live Expert Sessions ➚ 🔒Explore the Full Masterclass ➚ Enjoying the Dr. GPCR Podcast? Leave a Review. Leave a quick review to help more scientists find the show—and help us keep improving every episode. It takes <60 seconds and makes a big difference. ★ Review on Apple Podcasts ★ Rate on Spotify ✉️ Send feedback to the team Thanks for listening to this podcast episode Follow us on your favorite Podcast Player << Previous Podcast Episode Next Podcast Episode >>

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

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