Like a receptor

It is a bad hair day for Lefkowitz, as I learned this morning form the SciAm podcast “The 2012 Nobel Prize in Chemistry“. And since there was also a brief mentioning of migraine in this podcast, I thought I get into this.

This Nobel prize (why for Chemistry not for Physiology and Medicine, can anyone explain?) was awarded to Brian Kobilka and Robert Lefkowitz for their work on how G-protein–coupled receptors function. If you knew this already, you probably also have heard that G-protein–coupled receptors (GPCRs) are targets for as many as 50% of prescription medicines. So here is the story on migraine as an example.

I am not at all an expert on “wet” biochemistry. But looking at migraine from a mathematical perspective, I got interested in neuropeptides, that is, small protein-like molecules that neurons use to communicate (similar like the larger neurotransmitters). Simulating the communication between brain areas based on mathematical models is a big issue in mathematical biosciences, applications in neurology in particular. Anyway, I might dig into this another time. Back to neuropeptides and G-protein–coupled receptors.

Generally, peptides can act at G-protein–coupled receptors, so here we go. Several neuropeptides—maybe most famous substance P (‘p’ like powder but also like pain) and furthermore the neuropeptides neurokinin A and calcitonin gene-related peptide (CGRP)—can be released from the activated fifth cranial nerve, the trigeminal nerve. Only the latter (CGRP) however, is elevated during the headache phase of migraine and therefore this pro-inflammatory neuropeptide may cause the headache pain.

So obviously researchers (well, some might also say pharmaceuticals companies) started to look for a selective CGRP receptor antagonist. Even if the release of CGRP is a rather downstream event in the pathogenic cascade of migraine, such an antagonist would be perfect to investigate the role of CGRP in migraine headaches.

Several CGRP antagonists were found within the last years, known as gepants (or for the experts: BIBN4096BS (named later Olcegepant) and BI 44370 TA, both from Boehringer Ingelheim Pharmaceuticals, or MK-0974 (Telcagepant) and an earlier version MK-3207, both from Merck). So novel therapeutic mechanism in migraine treatment seem to be ready for clinical use. The promise was nothing less than a major turning point in the treatment of migraine in the coming years. We have seen one before, in the 1990, with the introduction of triptans. Triptans are serotonin receptor agonists acting on the 5-HT1B/1D receptor sites (but not antagonist, in case you got confused). Triptans inhibit the release of pro-inflammatory neuropeptide such as CGRP and also substance P. They also cause vasoconstriction of the dilated blood vessels in the head, while gepants do not show any vasoconstrictor activity. Vasoconstrictor activity is considered bad, so gepants might beat triptans (to cut a complicated story short).

Unfortunately, clinical development programs of Telcagepant had to be stopped as it became clear from findings—including some in a completed six-month Phase III study (when the treatment was given to large groups of people)—that liver toxicity issues exist. At least they did when used as preventives, but in any case the further development would have been much complicated by this. So it was stopped. You might call this Good Clinical Research Practice (GCRP*). Results from studies with BI 44370 TA seem to not have yet raised any serious concerns. Further studies are ongoing with this component.

What has this got to do with how G-protein–coupled receptors function, i.e., with the 2012 Nobel Prize in Chemistry?

CGRP (Calcitonin gene related peptide) should not be confused with a G-protein–coupled receptor (GPCR, its a permutation, haha). But CGRP (the elevated neuropeptide that might cause pain in migraine, still remember this?) mediates its effects through a G protein-coupled receptor. And although I might confuse you completely—it did confuse me initially—, the receptor of this neuropeptide is called calcitonin receptor-like receptor (CRL, well, together with a even more important receptor activity modifying protein, RAMP1, CRL forms the CGRP receptor). Where there is a calcitonin receptor-like receptor, there is also a calcitonin receptor (CTR).  These are just  two of the 15 human family B GPCRs, also called the secretin family. And there is the family A GPCRs. (All G-protein–coupled receptors share a common signalling mechanism by their common molecular architecture with seven transmembrane helices. GPCRs have first been classified into six seemingly unrelated families, but there is the possibility of a common evolutionary origin for all of them, a superfamily).

Bye now you have been probably SHIFT CTRL-out of this blog post, unless you really like receptors (which I don’t, bye the way, I like math much more but you have to work your way through those types of things, if you what to make mathematical models). In any case some of you made it to the end, I hope. The identification of all these parts, which have this confusing names and acronyms (of course there are even many more), established that GPCRs are an essential component in a wide variety of physiological processes, migraine pathogenesis being only one of them.

 

tl;dr? Summary:

  • GPCR: a receptor with seven-transmembrane domains; stuff you get a Nobel Prize for.
  • CGRP: a pro-inflammatory neuropeptide that might cause pain in migraine and acts at a GPCR.
  • GCRP: Good Clinical Research Practice, that stopped research on how some CGRPs act on GPCRs.

 

 

Footnotes

* No, I am making all these acronyms up (but this was a post edit, Oct 11). To make matters worse, my own work is on certain cortical activity patterns in migraine that are usually thought of not occurring in the frontal lobe. But I think they do occur there, too.  The frontal lobe starts with the anterior wall of the central sulcus. Yet, the sulcus is, of course, not seen if you look at (non-inflated) fMRI images of the cortex, but since the frontal lobe continues onto the gyrus precentralis, which is seen in these images and its acronym is: GPrC. So, I also read at times GPrC in the literature, too.

 

Markus Dahlem forscht seit über 20 Jahren über Migräne, hat Gastpositionen an der HU Berlin und am Massachusetts General Hospital. Außerdem ist er Geschäftsführer und Mitgründer des Berliner eHealth-Startup Newsenselab, das die Migräne- und Kopfschmerz-App M-sense entwickelt.

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  1. Thank you for your article. I get headaches. They have been given different names but I prefer “cluster” as mine fit the description. I take sumatriptan with much success. The insurance and the doctors are loathe to prescribe more than 9 pills per month citing the lack of studies. I am guessing the insurance for financial reasons. I look for alternate therapies because I often run out of medicine. I recently found a neurologist that doubled my monthly allotment. I bring this to your attention because I expect there are others like me that have to suffer because of the 9 pill limit. I am advocating for them and maybe myself if my doctor ever changes his mind. You seem to be in a position of bringing this information to the forefront. I hope it is something might be willing to do. My sincerest thanks. Bob

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