Strategic Partner(s)

Debbie Hay: Class B GPCRs, RAMPs, and the Migraine Pharmacology Gap

Class B GPCRs represent one of the smaller subfamilies in the GPCR superfamily - just 15 receptor genes - yet they govern a disproportionately wide range of physiology, from calcitonin-mediated bone remodeling to the peptide signaling networks underlying migraine. Their pharmacological complexity is amplified by receptor activity modifying proteins (RAMPs), three single-pass membrane proteins that associate with these receptors to create pharmacologically distinct complexes. A single receptor can form three different functional units depending on which RAMP is present, and those distinctions determine ligand selectivity, signaling output, and ultimately drug targeting.

Hay examines the molecular pharmacology of the calcitonin receptor and calcitonin-like receptor - with particular focus on their RAMP-dependent behavior and their roles in CGRP-mediated migraine. She argues that the field has moved faster than the evidence warrants: approving antibodies and small molecules against receptor targets whose full selectivity profile remains uncharacterized. For Hay, who has studied RAMPs since they were first described and when working on them was a high-risk research bet, the CGRP drug approvals are both a vindication and a reminder of how much foundational pharmacology the field skipped on the way to the clinic.

ABOUT THE GUEST

Hay is a professor of pharmacology at the University of Otago, New Zealand. Her research centers on the molecular pharmacology of class B GPCRs - specifically the calcitonin receptor and calcitonin-like receptor - and their interactions with RAMPs. She has worked across pharmaceutical, biotechnology, and academic settings, including a research placement at GlaxoWellcome, a PhD in molecular pharmacology at Imperial College London, and 17 years at the University of Auckland, where she led her own laboratory and served as head of department. Her current work addresses one of the central unsolved problems in RAMP pharmacology: developing tools selective enough to distinguish between closely related receptor-RAMP complexes in disease-relevant tissues.

SCIENTIFIC THEMES OF THE CONVERSATION

RAMP-dependent pharmacological diversity in class B GPCRs
The selectivity problem in CGRP-targeted migraine therapies
Obligatory receptor heterodimers and the limits of current characterization tools
Structural biology of RAMPs - allosteric modulation over direct ligand contact
Reproducibility and target validation as prerequisites for meaningful GPCR pharmacology
Career navigation across academia, big pharma, and biotech

KEY INSIGHTS FROM THE CONVERSATION

Fifteen Genes, Far More Than Fifteen Pharmacologies

Class B GPCRs are a small family by gene count, but RAMP association multiplies their pharmacological diversity considerably. Each of the three RAMPs can pair with a given receptor to produce a distinct complex - different ligand selectivity, different signaling profile, different therapeutic implications. The field routinely treats these complexes as interchangeable, but Hay argues they are not, and that assumption has downstream consequences for how drugs are characterized and how trial failures are interpreted.

The Erenumab Selectivity Problem

Erenumab, the first monoclonal antibody approved against a GPCR complex, targets the CLR-RAMP1 receptor - the canonical CGRP receptor in migraine. But Hay makes the case that the antibody's selectivity for this complex over the closely related CTR-RAMP1 complex has never been adequately demonstrated. Shared structural features between the two receptor complexes, combined with the known pharmacology of CGRP at CTR-RAMP1, suggest the drug may be less target-selective than its approval label implies - and that effects attributed to one target may partly involve another.

mRNA Cannot Tell You Where the Functional Dimer Is

For obligatory heterodimers like RAMP-receptor complexes, knowing which component genes are expressed in a cell tells you surprisingly little. The functional unit is the assembled complex at the cell surface, and that assembly is not predictable from transcript data - even at single-cell resolution. Hay frames this as one of the foundational unsolved problems in RAMP pharmacology: without tools to visualize and quantify the actual complex in native tissue under disease conditions, target validation remains incomplete and the pharmacology remains unresolved.

RAMPs Act Allosterically - Not Through Direct Ligand Contact

Structural data from the CLR and CTR receptor families has produced a result that surprised the field: RAMPs contribute almost no direct molecular contacts to the bound ligand. Their influence on receptor pharmacology appears to be primarily allosteric - subtly reshaping the GPCR binding site rather than contributing their own contact surface. This reframes the design challenge for RAMP-selective compounds: the differences between receptor complexes are conformational and fine-grained, not structurally obvious, making ligand selectivity considerably harder to engineer than a direct-contact model would predict.

The Migraine Pharmacology Gap

CGRP is elevated in migraine, infused CGRP triggers migraine-like headache in susceptible individuals, and drugs targeting that pathway can abolish chronic migraine entirely for some patients - while doing nothing for others. The mechanistic story remains incomplete: which receptor complex mediates which symptom, why the response is so variable across patients, and what the CGRP system is actually doing in the peripheral and central nervous system. For a condition affecting up to 20% of women worldwide, Hay notes, the research investment in understanding the receptor-level biology is strikingly insufficient.

Burning Curiosity as the Non-Negotiable

Hay's advice to junior scientists distills to a single criterion: if the curiosity isn't deep enough to outlast the failures, the career won't hold. Grant rejections, papers rejected seven times, experiments that don't replicate - these are not exceptional events but structural features of a scientific life. The scientists who persist, in her framing, are not the ones who feel less pain from those setbacks, but the ones for whom the pull toward the question is stronger than the push of the failure. She gives herself one day to be unhappy about a rejection. Then she moves on.

EPISODE TIMELINE

Timestamps are AI-generated from the episode transcript and are approximate. Minor offsets may occur in the final edited episode.

00:00 Welcome and episode announcements
01:40 Introduction - Hay
02:43 Career trajectory - from vet school to GPCR pharmacology
07:55 First encounter with GPCRs at GlaxoWellcome - and how RAMPs entered the picture
11:03 Class B GPCRs - why 15 receptor genes produce far greater pharmacological diversity than expected
13:30 CGRP, migraine, and the first antibody approved against a GPCR complex
18:50 Migraine as an invisible disability and the limits of what current treatments explain
20:41 Obligatory dimers and the challenge of mapping receptor complexes in disease-relevant tissue
23:54 Tools the field needs - antibody selectivity, selective ligands, and bimolecular fluorescence complementation in vivo
26:42 Structural data and what it reveals about how RAMPs actually modulate receptor pharmacology
29:43 Are GPCRs still good drug targets - and what is missing from class B pharmacology
31:41 Reproducibility, target validation, and the cost of science that cannot be repeated
34:53 Career advice - burning curiosity, celebrating wins, and being kind

SELECTED QUOTES

"I can't pick a favorite because these are such complex receptors and we fundamentally don't understand which are most important. Because we don't have selective ligands."

"We have to know where our receptor is in our tissue of interest, in our disease condition, and how it is signaling - because that is what we need to target."

"There is too much out there that is not replicable. And it causes careers to die. It's just not fair on the junior scientists who then follow up on that work to find it can't be repeated."

"If you've got that deep, deep drive still to get over those failures and pick yourself up, and that's a strong enough fire burning, then you will succeed."

About this episode

Dr. Debbie Hay is presently a professor at the Department of Pharmacology and Toxicology at the University of Otago after spending 18 years at the University of Auckland. Her work is primarily focused on class B GPCRs and their interactions with RAMPs. Debbie obtained a Ph.D. in Molecular Pharmacology from Imperial College London in the UK. She has gained experience from working in academia and at GSK as an industrial trainee.

Join me and learn more about Debbie’s career and what she learned through her experiences as a scientist.

Dr. Debbie Hay on the web