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The biggest signal is not the same as the truest one. Jane Lamerdin and Gaurav Agrawal of Eurofins DiscoverX on what actually makes a GPCR assay trustworthy. Overexpress a receptor and you get a big, convenient readout that drifts away from what happens in a living cell. Across nearly three decades of building cell-based assays, Lamerdin and Agrawal have learned that physiological relevance, not raw expression, is the real benchmark, and increasingly it is what regulators expect too. This conversation moves from the company's roots in cyclic AMP and arrestin biology to the receptors that refuse to yield an assay, the long road from a discovery screen to potency and lot release, and why the obesity drug wave brought the largest target class back to the front of drug discovery. What you will take away: Why physiological relevance beats maximal expression, and how that raises the technical barWhat it takes to move one assay from discovery all the way to potency and lot releaseWhy some GPCRs, from adhesion receptors to orphans stuck in the ER, refuse to cooperateHow decades of documented failures keep a portfolio from reinventing dead endsWhy obesity and GLP-1 biology put GPCRs back at the center of drug discovery Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/Eurofins DiscoverX: https://www.ecosystem.drgpcr.com/eurofins-discoverxMembership and Pricing: https://www.ecosystem.drgpcr.com/university-pricing

Adhesion GPCRs are the largest receptors in the human genome — and until recently, no one was certain they coupled to G proteins at all. Boucard is working to change that, one synapse at a time. Antony Boucard didn't plan to be a scientist. He was heading toward medical school — fresh from social work in Nicaragua, where he built wood-burning ovens for women's cooperatives, and years of service in the Canadian Navy Reserve — when a summer in a biochemistry lab changed his trajectory entirely. He turned down his medical school acceptance and never looked back. After graduate training at the Université de Sherbrooke, a postdoctoral fellowship in Thomas Südhof's Nobel Prize-winning lab (first at UT Southwestern in Dallas, then at Stanford) opened a new research direction: the molecular code governing synapse formation. A chance experiment — testing whether a cell adhesion molecule he was studying might bind to a GPCR — yielded a result that Südhof himself didn't believe at first. Both proteins, it turned out, were independently known to bind alpha-latrotoxin, the toxin from black widow spider venom. No one had thought to ask whether they interacted with each other. That question has defined Boucard's lab ever since. Now at UNAM in Mexico City — where no lab was working on adhesion GPCRs when he arrived — he is building a research program that connects these colossal, largely orphan receptors to synapse specificity, addiction, autism, schizophrenia, bipolar disorder, and cancer. The conversation covers the science, the serendipitous path behind it, and what it looks like to pioneer a research field in a place no one expected. Why adhesion GPCRs are structurally unlike any other GPCR family — sprawling N-terminal domains, autoproteolytic processing, up to 1,000 amino acids — and what made them so difficult to work with for so longHow alpha-latrotoxin from black widow spider venom became the unexpected clue connecting a cell adhesion molecule and a GPCR into the same intercellular complexWhat synapse formation reveals about adhesion GPCR function — and how addiction, autism, schizophrenia, and cancer all converge on the same receptor biologyWhy Boucard left Stanford and UT Southwestern to build a lab at UNAM, and what it means to recruit from scientific communities that larger institutions overlookThe assays the lab uses to probe adhesion GPCR biology: BRET, FRET, microscopy, flow cytometry, and custom protein engineering strategies to solubilize membrane-anchored ligandsThe dream tool he can't build yet — a nanoscale real-time camera navigating the cell surface — and why cryo-EM snapshots still miss the most important part Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/ Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricingWeekly News: https://www.ecosystem.drgpcr.com/gpcr-weekly-news

Frizzled receptors look like GPCRs — but the field is split on whether they actually are. Gunnar Schulte has spent 25 years building the case, one receptor at a time. Schulte is a professor at Karolinska Institute in Stockholm, where his lab investigates Wnt–frizzled signaling at the molecular level. His research maps G-protein coupling specificity across all 10 frizzled subtypes, develops conformational biosensors to detect receptor activation, and searches for small molecules that could finally make frizzled receptors pharmacologically tractable. In this conversation, he walks through the evidence — what the conformational data show, why the Wnt ligand problem has stalled the field for decades, and how a compound originally designed for Smoothened became the closest thing frizzled pharmacology has to a starting point. Why each frizzled subtype couples to a different G protein — and why that distinction changes how the field should think about targeting themWhy 19 Wnt ligands remain almost impossible to work with, and what the lipid modification problem costs drug discoveryHow SAG1.3, a Smoothened agonist, became the first small molecule to activate frizzled 6 as a partial agonistWhat conformational sensors reveal about frizzled activation — and why Schulte considers this his strongest argument for their GPCR identityHow disheveled and G proteins may compete for receptor access through conformational selection Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/ Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricingWeekly News: https://www.ecosystem.drgpcr.com/gpcr-weekly-news

Same binding affinity. Same target. One compound worked in vivo. The other did nothing. The answer was how long each molecule stayed on the CRF receptor — seven hours versus fifteen minutes — and no one had thought to measure it. Sam Hoare spent 15 years at Neurocrin Biosciences before founding PharmaChanics, a pharmacology data analysis consultancy built on one conviction: most GPCR teams are collecting data they don't know how to analyze. In this conversation, Hoare walks through the off-rate discovery that redirected an entire drug program, the signaling kinetics framework he developed to fill a gap no one had formally acknowledged, and what it actually takes to move from industry scientist to independent consultant. Along the way: why GPCRs are the most tractable system in pharmacology — and why that still isn't enough if the analysis is wrong. How receptor residence time — not affinity — determined which CRF compound reached Phase 2Why time-course signaling data is routinely collected but almost never analyzed with the rigor applied to dose-response curvesWhat 15 years of GPCR drug discovery taught Hoare about the gap between understanding a receptor and making a drug for itHow early-career researchers can leverage deep target expertise to build a consulting practiceThe three aha moments that have kept a pharmacological data analyst motivated across a 30-year career Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricingWeekly News: https://www.ecosystem.drgpcr.com/gpcr-weekly-news

Lefkowitz was told in 1973 that hormone receptors were a figment of his imagination. The work that proved otherwise became the molecular foundation of GPCR pharmacology. Nobel laureate Robert Lefkowitz traces the full arc of GPCR discovery — from developing the first radioligand for the beta-adrenergic receptor to purifying it, cloning it, and watching a sequencing run reveal structural homology with rhodopsin that nobody in the field had predicted. That 1986 paper established the GPCR superfamily. The same system yielded the GRK family and the beta-arrestins. This conversation is also about the human architecture behind that science: how a Vietnam War draft assignment in 1968 redirected a physician toward a question the field wasn't sure was real, what 18 months of unbroken failure at the NIH taught him about research, and why he argues that if 50% of your experiments succeed, you are not working on hard enough problems. How a Vietnam War draft sent a physician to the NIH — and gave rise to 50 years of GPCR receptor pharmacologyWhy Lefkowitz chose the beta-adrenergic system, and why he considers it the smartest scientific decision of his careerThe cloning race against Genentech: the "stupid idea" that worked and the intronless gene that ended the competitionHigh output vs. low output failure — how to find the research territory between trivial problems and intractable onesWhat the Nobel call at 5 AM actually felt like: not jubilation, but relief — and a tear when he learned who he'd share it with Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/ Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricingWeekly News: https://www.ecosystem.drgpcr.com/gpcr-weekly-news

Most GPCR antibody failures are silent. The signal looks clean, the band is there, the experiment moves forward - until someone runs a knockout control and the signal is still there. Lin and Ball have spent years building reagents for exactly this problem, and this conversation gets into the details of what reliable GPCR antibody characterization actually requires. Chia-Yi Lin and Alexander Ball are scientists-turned-industry professionals at GeneTex, a company that has shifted its entire new antibody production to recombinant monoclonal technology since 2019. In this conversation, they trace the arc from GeneTex's founding by cancer biology researchers in 1990s Texas to its current position as a growing source of characterized GPCR research reagents. The discussion covers why GPCR targets are especially difficult immunogen design problems, what five-pillar antibody characterization looks like for receptors like LGR5 and the chemokine receptor family, and why the word "characterized" may be more scientifically honest than "validated" when describing what an antibody data sheet actually tells you. Ball's path from medicine to the bench to industry - and Lin's from stem cell biology to leading international operations at GeneTex - brings a rare dual perspective to a problem that most researchers only see from one side. Key topics covered: Why GPCR family homology - including the 75% sequence identity between CXCR1 and CXCR2 - makes immunogen selection the critical upstream decision in antibody development, often determining success or failure before a single experiment is run What five-pillar characterization looks like in practice: KO and KD validation, comparable antibody testing, cell fractionation, tissue orthogonal testing, and GPCR virion arrays from CDI Labs How recombinant monoclonal antibodies solve the batch variability problem that polyclonal production cannot - and why a sequence defined in a plasmid changes reproducibility for the entire field The LGR5 story: how one leucine-rich repeat GPCR critical to intestinal stem cell biology became GeneTex's defining early challenge - and why Ball's company president went pale when the target came up Why Ball and Lin encourage researchers to contact the company directly before purchasing, what questions to ask, and how a free GPCR antibody sample program is actively connecting the community with reagents that need real-system testing Dr. GPCR Links and Resources Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/Membership and Pricing: https://www.ecosystem.drgpcr.com/university-pricingWeekly News: https://www.ecosystem.drgpcr.com/gpcr-weekly-news

Most receptors come with a history. Remulate came with a name — and almost nothing else. Dr. Beatriz Redondo, group leader at the University of Leipzig, has spent the last nine years building the first systematic characterization of adhesion GPCRs in Drosophila, including three receptors so new they were named after condiments. What she's constructing isn't just a receptor profile — it's a method for doing discovery when the tools don't exist yet. Dr. Redondo uses CRISPR, genetic tagging, and in vivo behavioral assays to place and characterize adhesion GPCRs in a system where generations turn over in weeks. Her work on remulate — a neuronal adhesion GPCR with a human ortholog linked to vascular malformations and blood-brain barrier dysfunction — is among the first of its kind in any organism. Key takeaways: Why Drosophila remains a productive system for receptor discovery in the genomics eraHow CRISPR and epitope tagging replace antibody-based tools for understudied GPCRsWhat nocifensive behavior in larvae reveals about remulate's neuronal functionHow basic science in an insect model connects to vertebrate disease biologyWhat it looks like to characterize a receptor from scratch — with no prior literature to build on Dr. GPCR University — live and on-demand courses for scientists working on real discovery problems: https://www.ecosystem.drgpcr.com/gpcr-university This episode is supported by Eurofins DiscoverX and GeneTex: https://www.ecosystem.drgpcr.com/eurofins-discoverx | https://www.ecosystem.drgpcr.com/genetex

What if two nearly identical GPCRs make a worse chimera than two receptors from completely different classes? Charlotte Crauwels is building computational tools to find out why — and to predict which designs will work before they reach the bench. Crauwels develops in silico pipelines for chimeric GPCR design at the Free University of Brussels. Her work sits at the interface of computational prediction and experimental validation, addressing a problem the field has struggled with for decades: chimeric constructs are powerful but unpredictable, and the data surrounding them is scattered, inconsistently named, and poorly annotated. After spending over a year collecting and standardizing published chimeric GPCR data, she built GPCR ChimeraDB — one of the first public databases dedicated to these constructs. Key takeaways: How chimeric GPCRs can deorphanize receptors and reveal signaling pathways that were previously inaccessibleWhy computational ranking of chimeric candidates replaces trial-and-error in the labWhat inconsistent nomenclature and missing annotations cost the field — and how better data sharing changes the gameWhy the feedback loop between computational and experimental scientists is non-negotiable for GPCR research Dr. GPCR Links & Resources Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricingWeekly News: https://www.ecosystem.drgpcr.com/gpcr-weekly-news

Every beta-2 agonist ever tested for muscle growth hits the same wall: desensitization. Dr. Tore Bengtsson built one that doesn't. A professor at Stockholm University and founder of Atrogi, Dr. Bengtsson has spent 25 years studying how beta-adrenergic receptors regulate metabolism, muscle, and brown fat. His lab developed 1,500+ compounds that activate beta-2 through distinct signaling pathways, and one is now heading into Phase 2 clinical trials. He shares how a "failed" experiment cracked the problem, why incretins only address half of metabolic disease problems, and what muscle loss after 50 means for drug discovery strategy. Key takeaways: Classical beta-2 agonists fail because desensitization shuts down the responseSelectively activating specific signaling pathways from one receptor can produce entirely different outcomesIncretins reduce energy intake — but the energy expenditure side remains wide openThe correlation between muscle mass and longevity is one of the most underserved areas in metabolic medicine🔗 Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/ 🎓 Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricing 📰 Weekly News: https://www.ecosystem.drgpcr.com/gpcr-weekly-news

Dr. Joseph Kim solved cryo-EM structures of mu and kappa opioid receptors bound to the same small molecule — and found it does something different at each one. In this conversation, Dr. Kim walks through his transition from cryo-electron tomography to GPCR structural biology in Ashish Manglik's lab at UCSF, the strategy behind solving inactive-state receptor structures, and why his favorite GPCR — the galanin receptor — has resisted every small-molecule screen thrown at it. Key takeaways: How one molecule acts as an antagonist at mu and an inverse agonist at kappaWhy the galanin receptor's peptide binding mode blocks conventional drug discoveryWhat it takes to switch fields with no prior biochemistry trainingHow building tools on "vanilla" GPCRs prepares you for exotic targets 🔬 Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/ 💰 Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricing 📰 Weekly News: https://www.ecosystem.drgpcr.com/gpcr-weekly-news

How does ligand binding at the extracellular pocket of a GPCR reshape signaling on the intracellular side? Biased agonism is often measured through pathway activation assays, but the structural origin of ligand bias remains difficult to trace. Can molecular simulations reveal the communication routes that link ligand binding to G protein or arrestin signaling? In this conversation, computational biologist Anita Niveda explores how molecular dynamics and network analysis can map allosteric communication within GPCRs—revealing how microscopic structural pathways relate to macroscopic signaling outcomes. From discovering bioinformatics as an undergraduate to developing computational methods for quantifying ligand bias, the discussion moves through the scientific thinking behind modeling receptor signaling, collaborations between academia and industry, and how computational tools are becoming predictive instruments in drug discovery. Key Topics in This Episode How molecular dynamics simulations reveal communication pathways connecting ligand binding sites to G protein or arrestin interfaces Why mapping allosteric communication networks helps explain biased agonism in GPCR signaling What computational strategies can quantify ligand bias directly from receptor structures How receptor subtype selectivity emerges from subtle structural and dynamic differences in binding pockets Why academic–industry collaborations can accelerate method development in receptor pharmacology What career decisions shape the path from computational biology training to drug discovery roles Timestamps 0:00 A structural question behind ligand bias1:30 Introduction and scientific background3:40 Discovering bioinformatics and computational biology7:30 First encounters with GPCR structural biology9:40 Finding and choosing a postdoctoral lab16:40 Entering GPCR research and allosteric communication18:20 Quantifying ligand bias using simulations20:00 Mapping signaling pathways through receptor residues23:30 Academic–industry collaboration with Boehringer Ingelheim27:00 Moving from academia to industry research35:00 Interviewing and transitioning into biotech45:00 Aha moments in computational GPCR research50:00 The diversity of GPCR families and signaling biology Keywords: GPCR podcast, GPCR signaling, biased agonism, drug discovery, receptor pharmacology

Conserved neuropeptide Y GPCRs orchestrate both feeding and mating behaviors in mosquitoes, with direct translational parallels to human gut-brain signaling. Quick Summary Learn how receptor internalization and neuropeptide GPCR signaling underlie the regulation of mosquito host-seeking and reproduction. Dr. Laura Duvall details the use of CRISPR-based assay development and fluorescence-driven phenotyping to connect molecular manipulation to whole-animal behavior. Her approach provides actionable insights for gpcr drug discovery and tools to dissect homologous pathways across model systems, with implications for pharmacology research targeting vector-borne disease transmission. Key Takeaways Neuropeptide Y GPCRs modulate both host attraction and mating in Aedes aegypti. CRISPR and fluorescence assays enable precise behavioral phenotyping in vivo. GPCR-targeted compounds designed for humans can modulate mosquito receptors. NPY receptor expression in mosquito gut mirrors mammalian gut-brain signaling axes. Automated behavioral assays combined with machine learning sharpen data resolution and reduce human bias. Dr. GPCR Links & Resources Explore essential resources: Dr. GPCR Ecosystem Membership & Pricing Weekly News Advance your research—discover the power of Dr. GPCR Premium. About the Guest Dr. Laura Duvall earned her B.A. in Biochemistry and Biological Basis of Behavior from the University of Pennsylvania, followed by a PhD at Washington University in St. Louis, where she explored neuropeptide regulation of circadian behavior in Drosophila. Transitioning from fruit flies to mosquitoes, she pursued postdoctoral research at Rockefeller University with Leslie Vosshall, focusing on the molecular regulation of feeding and mating behaviors in Aedes aegypti. In 2019, she established her independent laboratory at Columbia University's Department of Biological Sciences and the Zuckerman Institute. Dr. Duvall’s work is recognized by awards including the Beckman Young Investigator Award, Klingenstein-Simons Fellowship in Neuroscience, and the Pew Scholars Program, reflecting her drive to unravel the complex signaling mechanisms that govern mosquito and broader animal behavior. Guest on The Web LinkedIn: https://www.linkedin.com/in/laura-duvall-28a03485/ Google Scholar: https://scholar.google.com/citations?user=Vk3KGSoAAAAJ&hl=en Lab: https://www.duvalllab.com/

Key Takeaways How does the precise localization of GPCRs in lipid rafts reshape drug discovery strategy? Examine implications for functional assays and therapeutic innovation. Explore the pivotal role of GPCR-lipid raft compartmentalization in receptor signaling, desensitization, and pharmacology research. Dr. Keyvan Sedaghat discusses assay approaches, regulatory mechanisms, and the translational impact of bitter taste receptors beyond sensory biology. Leveraging decades of experience in assay development and database creation, he offers actionable insights for researchers optimizing GPCR drug discovery pipelines. Compartmentalization of GPCRs in lipid rafts directly influences receptor signaling and drug response. Desensitization pathways of dopamine D1 receptors depend on precise phosphorylation domains—challenging classical paradigms. Bitter taste receptors demonstrate functional relevance in non-gustatory tissues with emerging therapeutic applications. Database-driven research accelerates the identification of receptor-microdomain interactions for novel targets. Integration of computational modeling and biochemical validation is essential for advancing GPCR assay strategies. Dr. GPCR Links & Resources Access the Dr. GPCR Ecosystem at https://www.ecosystem.drgpcr.com/ for community, tools, and databases. Details on Membership & Pricing: https://www.ecosystem.drgpcr.com/university-pricing GPCR Weekly News: https://www.ecosystem.drgpcr.com/gpcr-weekly-news Explore Dr. GPCR Premium for expanded translational resources and networking. About the Guest Dr. Keyvan Sedaghat holds a pharmacy degree and a PhD in cellular and molecular medicine, specializing in pharmacology, from the University of Ottawa. With over two decades of academic experience, he has served as a professor, senior lecturer, and chief scientific officer in the pharmaceutical and cosmetic industries. Dr. Sedaghat’s work spans peer-reviewed publications and editorial roles across journals in molecular pharmacology, cell signaling, and G protein-coupled receptors. His scientific drive centers on unraveling molecular mechanisms underlying GPCR function and translating those findings into effective teaching, research, and drug discovery strategies. Guest on the Web: LinkedIn Google Scholar

Episode Summary Potent in vitro hits often fail in vivo—Martin Marro details how robust assay choice and pathway deconvolution can revive GPCR drug discovery programs. Listeners will learn practical approaches to assay development for GPCR drug discovery, the pitfalls of calcium readouts, and how identifying pathway bias impacts translational success. Dr. Marro shares his experience bridging in vitro–in vivo gaps, refining selection flowcharts, and leveraging pharmacology research to drive clinical candidates. His strategic perspective is rooted in years of leading multimodal discovery teams in pharma and biotech. Key Takeaways Assay selection critically shapes the trajectory from hit to clinic.Calcium and IP1 assays may not predict in vivo efficacy for all Gq-coupled receptor targetsAlternative pathway analysis may be essential for mechanism elucidation.Persistence in probing beyond standard readouts can rescue high-profile discovery programs. Team structure and collaborative problem-solving are pivotal in resolving translational bottlenecks. Explore Dr. GPCR Resources - Dr. GPCR Ecosystem - Membership & Pricing - Weekly News Explore the full depth of GPCR resources, events, and member-exclusive tools with Dr. GPCR Premium. About the Guest Dr. Martin Marro leads the Cell Pharmacology group in the DOCTA division at Lilly’s Seaport Innovation Center in Boston, MA. Trained as a pharmacologist, Dr. Marro has accumulated over 20 years of experience spanning large pharmaceutical firms—including GSK, Novartis, and Lilly—and innovative biotech such as Tectonic Therapeutic. He holds deep expertise in early drug discovery across small molecules, peptides, and antibody therapeutics for metabolic, cardiovascular, and gastrointestinal diseases. Dr. Marro’s research has been central to the discovery and characterization of multiple clinical candidates, with a focus on GPCR target validation, receptor pharmacology, and translational assay strategies. He played a key role in patenting and developing novel fatty acid-conjugated GLP-1 receptor agonists. Driven by the challenge of translating robust in vitro science into clinical proof-of-concept, Dr. Marro’s leadership continues to impact the field of GPCR drug discovery. Keywords: gpcr podcast, assay development, pharmacology research.

GPCR tools don’t move the field forward unless researchers can actually use them. This episode breaks down how collaboration turns probes into progress. Summary In the final episode of this series, David Hodson, Johannes Broichhagen, and Maria Majellaro unpack how academic labs and Celtarys Research partnered to scale fluorescent probes, improve assay development, and support gpcr drug discovery. The conversation spans receptor internalization, fluorescence assays, tech transfer realities, and why tool availability—not just invention—drives translational pharmacology research. Key takeaways Why accessibility defines the real impact of GPCR tools How industry enables scalable assay development Lessons from receptor internalization studies in complex tissues What makes academia–industry collaborations actually work Read more here: https://www.ecosystem.drgpcr.com/dr-gpcr-podcast/scaling-glp-1-receptor-tools-through-academia–industry-collaboration