Dr. GPCR Podcast

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 bar
What it takes to move one assay from discovery all the way to potency and lot release
Why some GPCRs, from adhesion receptors to orphans stuck in the ER, refuse to cooperate
How decades of documented failures keep a portfolio from reinventing dead ends
Why obesity and GLP-1 biology put GPCRs back at the center of drug discovery

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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 long
How alpha-latrotoxin from black widow spider venom became the unexpected clue connecting a cell adhesion molecule and a GPCR into the same intercellular complex
What synapse formation reveals about adhesion GPCR function — and how addiction, autism, schizophrenia, and cancer all converge on the same receptor biology
Why Boucard left Stanford and UT Southwestern to build a lab at UNAM, and what it means to recruit from scientific communities that larger institutions overlook
The assays the lab uses to probe adhesion GPCR biology: BRET, FRET, microscopy, flow cytometry, and custom protein engineering strategies to solubilize membrane-anchored ligands
The 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

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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 them
Why 19 Wnt ligands remain almost impossible to work with, and what the lipid modification problem costs drug discovery
How SAG1.3, a Smoothened agonist, became the first small molecule to activate frizzled 6 as a partial agonist
What conformational sensors reveal about frizzled activation — and why Schulte considers this his strongest argument for their GPCR identity
How disheveled and G proteins may compete for receptor access through conformational selection

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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 2
Why time-course signaling data is routinely collected but almost never analyzed with the rigor applied to dose-response curves
What 15 years of GPCR drug discovery taught Hoare about the gap between understanding a receptor and making a drug for it
How early-career researchers can leverage deep target expertise to build a consulting practice
The three aha moments that have kept a pharmacological data analyst motivated across a 30-year career

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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 pharmacology
Why Lefkowitz chose the beta-adrenergic system, and why he considers it the smartest scientific decision of his career
The cloning race against Genentech: the "stupid idea" that worked and the intronless gene that ended the competition
High output vs. low output failure — how to find the research territory between trivial problems and intractable ones
What 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

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