CGRP, PACAP and Beyond: Understanding Current and Future Migraine Treatment Targets – An Interview with Debbie Hay

By Lincoln Tracy | May 3, 2024 | Posted in

“We’re also trying to better understand the receptor pharmacology of the gepants and of the monoclonal antibodies against the CGRP receptor, because there isn’t as much of an understanding, at the receptor level, of how these drugs work as we think there is.

“So we’re looking at how they might affect different aspects of how these receptors function, such as how they might differentially affect cell signaling pathways that might be related to pain, or how they might affect how much of the receptor stays at the cell surface and how much of the receptor might be internalized inside the cell. Understanding subtleties such as these help us better understand mechanisms, which could ultimately help us refine and improve on the therapies we already have.”

– Debbie Hay

Debbie Hay, PhD, is a molecular pharmacologist and professor at the University of Otago in New Zealand. Her research focuses on proteins called G proteincoupled receptors (GPCRs), which continue to be a key focus of drug development efforts. Her work aims to contribute to developing medicines to treat migraine and other headache conditions.

In this Migraine Science Collaborative interview, she chats with Lincoln Tracy, PhD, a researcher and writer from Melbourne, Australia, about her path to becoming a molecular pharmacologist, her work on GPCRs, and the future of migraine treatment. The interview has been edited for clarity and length.

What was your path to becoming a molecular pharmacologist?

I started out in the UK and did my undergraduate degree in pharmacology at the University of Sheffield. While doing the degree I had the opportunity to do a year-long industrial placement at Glaxo Wellcome, before they merged with SmithKline Beecham to become GlaxoSmithKline, where I worked in the receptor pharmacology unit. This gave me a better understanding of molecular pharmacology, as I was working on screening for a G protein-coupled receptor.

I returned to my undergraduate degree around the time receptor activity-modifying proteins [RAMPs] were first described in a high-profile paper in Nature. We now know these proteins are a key component of CGRP receptors, but we didn’t know much about them at that time, and they became a big part of my molecular pharmacology course. This really spurred my interest because we always thought ligands bound to their receptors and that was it. But this changed the landscape and showed us that things could be more complex than we first thought. I was very keen to learn more about this.

Professor Debbie Hay

Professor Debbie Hay

I was looking at PhD opportunities as I got closer to the end of my undergraduate degree, and there was a PhD, focused on understanding more about the RAMPs, being advertised at Imperial College London. I was fortunate enough to get that position, and I’ve followed this path ever since.

Then, after I finished my PhD, there was an opportunity to take up a postdoctoral position at the Liggins Institute at the University of Auckland, which gave me a lot of flexibility in my research, enabled me to bring in my own grant funding, and to continue to look further into RAMPs and CGRP receptors.

What are you and your team currently working on?

CGRP receptors are still a core part of the business, so I’ve continued to work on these as well as related receptors such as the amylin and PACAP receptors. We work on all different kinds of G protein-coupled receptors, which are all interesting because they are complex for different reasons. There are a lot of fundamental things about these receptors that we’re still trying to understand, such as which exact receptor subtype is found in which exact location, and how these factors help us understand which receptors are the best targets for migraine treatment.

We’re also trying to better understand the receptor pharmacology of the gepants and of the monoclonal antibodies against the CGRP receptor, because there isn’t as much of an understanding, at the receptor level, of how these drugs work as we think there is. So we’re looking at how they might affect different aspects of how these receptors function, such as how they might differentially affect cell signaling pathways that might be related to pain, or how they might affect how much of the receptor stays at the cell surface and how much of the receptor might be internalized inside the cell. Understanding subtleties such as these help us better understand mechanisms, which could ultimately help us refine and improve on the therapies we already have.

What techniques do you use to answer these kinds of questions?

We use techniques ranging from cell culture dishes to humans, through international collaborative studies. We have our own lab here in New Zealand, but we collaborate widely with a lot of great labs around the world to tackle different aspects of these questions.

In our lab we’ll measure different intracellular signaling pathways in populations of cells and look at tissue slices to determine receptor expression in rodent and human samples. We also do some animal behavioral work to understand the effects of different ligands on the receptors, such as which ligands can produce migraine-like behavior and which ones can’t.

What are some of the challenges associated with your area of research?

The real challenges come at the molecular level because of the complexity of these receptors. For example, most G protein-coupled receptors have just one subunit, which is the core G protein-coupled receptor itself, but we also have the RAMPs that I alluded to earlier.

When we look at the CGRP receptor, we have our G protein-coupled receptor – CLR – and it pairs up with RAMP1. But we also have RAMP2 and RAMP3, and they can pair up with CLR as well. Then we have the calcitonin receptor, another G protein-coupled receptor, which binds to calcitonin, but this receptor can also pair up with each RAMP as well to create new receptor subtypes with a unique pharmacology. We end up having this mix and match of different G protein-coupled receptors with different RAMPs, creating a unique functional receptor complex. This makes it difficult to figure out exactly which receptor does what, as we have to understand both subunits together at the same time.

And then the PACAP receptors don’t have the RAMPs in the same way as the CGRP or calcitonin receptors, but there’s some emerging research suggesting that maybe they do need RAMPs, though that’s not very well understood. The PACAP receptors can also have splice variants, where different parts of the receptor are deleted or added in to make a different final receptor subtype at the cell surface, which is another way of increasing diversity. We have this interesting soup of different potential receptors that can be coded by these different genes or by these splicing events. But knowing exactly which of those molecular entities is responsible for which function is very difficult to pin down because there aren’t very good tools for understanding this.

What are the issues with the currently available tools?

Normally, we would try to understand the function of a receptor by making a knockout rodent model, but in this case, you would have to knock out both components or subunits of the receptor, not just one. And because each subunit can also pair with other receptors or RAMPs, you don’t get a clean phenotype. For example, if you knock out the calcitonin receptor, you knock out the function of calcitonin and of other ligands, so it becomes very difficult to interpret the data.

We can use antibody tools to understand where receptor subunits are expressed, but these tools are notoriously unreliable for G protein-coupled receptors. There are very few well-characterized antibodies for these receptors, so we don’t know how specific the antibodies are. And while RNA expression is a great tool, it only tells us the site of synthesis of the receptor; it’s not going to tell us what’s actually sitting on the cell surface as a functional protein. There are all sorts of challenges.

You penned a recent comment in response to a Personal View in the Lancet Neurology that looked at emerging options and prospects for treating migraine. Why is it so important to keep looking for new treatments?

The CGRP pathway drugs have been a huge advance in how we treat migraine, but we can always do better. We know these drugs work well for some patients, but not at all for others. And their costs remain a real barrier. There are people who can’t access triptans, which have been around for decades, let alone the new CGRP drugs, so there really is this unmet need around the globe. Having more options designed to target the mechanisms of migraine are vital because it is such a complex disorder.

In your comment you wrote that the PACAP ligand and receptor seem to be the closest to clinical application for migraine. Why do you feel this is the case?

That is based on the fact that there are preliminary, but positive, Phase 2 results from a migraine clinical trial for that target, which is supported by strong experimental data and human provocation studies. So, just on balance, the growing evidence base for that particular ligand-receptor system seems to be the closest to clinical application. Of course, there are still unknowns: What will the safety profile be? What will the data look like in Phase 3 clinical trials? We don’t know the answers yet, but of the options presented in the original Lancet Neurology article, that one seems reasonably promising. Other targets may have investigational agents in trials, but their effectiveness in migraine is not as clear-cut yet.

You also wrote of the need to determine the role of the amylin ligand and receptor in migraine. Can you elaborate on this?

This comes back to the complexity of the ligand-receptor family, which makes it challenging for us to understand what the best clinical strategy against these targets would be. The reason we discuss amylin in the context of migraine is because one of its receptors, AMY1, binds amylin, but it also binds CGRP equally well. AMY1 was called AMY1 because it was closely related to two other receptors that bind amylin, which are now called AMY2 and AMY3. So we have three amylin-responsive receptors, but one of them binds CGRP as well with really high affinity, so it could equally be a CGRP receptor.

Therefore, when we use amylin or an amylin agonist to provoke migraine-like attacks, it only tells us that an amylin-responsive receptor is activated, but it doesn’t tell us which one, and it doesn’t tell us about the physiological role of amylin because it’s only a pharmacological experiment. And so, more than 20 years later from first seeing that AMY1 binds CGRP as well as amylin, we still don’t know, in an in vivo setting, what the true endogenous ligand of the AMY1 receptor is. Is it amylin? Is it CGRP? Is it both, in different settings? And that’s one of the reasons we’re trying to figure out exactly where each receptor is and where each peptide is.

For example, if AMY1 is present in regions of the brain where CGRP is present in high abundance, but amylin is not there and is unlikely to reach those locations from the periphery, then it’s much more likely that in those brain locations AMY1 is relevant to CGRP, but not to amylin. But this situation could be different somewhere else in the body. We’ve recently found that, in the upper cervical dorsal root ganglion, amylin and CGRP are near the calcitonin receptor subunit of the AMY1 receptor, so maybe both peptide ligands are important in this location. Understanding the specific receptor-ligand interaction and context drives our clinical and drug discovery strategy.

You were recently part of a study that looked at CGRP in patients with post-concussion symptoms such as headache. How do you feel the growing awareness of the long-term effects of head trauma has helped research into headache and migraine?

The important thing to me here is that while we understandably focus much of our efforts and thinking on migraine, we have to remember that headache medicine is much, much broader than that. There are many different forms of primary and secondary headache with different degrees of disability and complex symptoms.

Raising awareness of headache disorders and their impact as a whole is important, but we really have to understand them, and I think that’s the key here. Each study like this provides a footprint in the sand on our journey of understanding these different headache disorders. We need to understand what is similar and what is different, and with all that information we can ultimately treat them better.

Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. Follow him on X (formerly Twitter) @lincolntracy

Image credit: iStock by Getty Images.

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Dr. Lincoln Tracy is a researcher and freelance writer from Melbourne, Australia. As a researcher, he uses data from an international clinical quality registry to explore burn injuries in Australia and New Zealand. As a freelance writer, he turns basic, translational, and clinical research into high-quality news, features, interviews, meeting reports, and podcasts. As a person, he is one half of one of two sets of twins in his family. Follow him on Twitter @lincolntracy.

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