Calcitonin/PAC1 receptor splice variants: a blind spot in migraine research

  • Trends Pharmacol Sci. 2023 Oct;44(10):651-663. doi: 10.1016/j.tips.2023.07.003.
Tayla A Rees  1 ,  Alejandro Labastida-Ramírez  2 ,  Eloisa Rubio-Beltrán  2
Affiliations
  • 1. School of Biological Sciences, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand. Electronic address: [email protected].
  • 2. Headache Group, Wolfson Center for Age Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
PMID: 37543479 DOI: 10.1016/j.tips.2023.07.003
Abstract

The neuropeptides Calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) and their receptors are linked to migraine neurobiology. Recent antimigraine therapeutics targeting the signaling of these neuropeptides are effective; however, some patients respond suboptimally, indicating an incomplete understanding of migraine pathophysiology. The CGRP- and PACAP-responsive receptors can be differentially spliced. It is known that receptor splice variants can have different pathophysiological effects in Other receptor-mediated pain pathways. Despite considerable knowledge on the structural and pharmacological differences of the CGRP- and PACAP-responsive receptor splice variants and their expression in migraine-relevant tissues, their role in migraine is rarely considered. Here we shine a spotlight on the Calcitonin and PACAP (PAC1) receptor splice variants and examine what implications they may have for drug activity and design.

Keywords
PACAP receptors; calcitonin gene-related peptide; calcitonin receptors; migraine; pituitary adenylate cyclase-activating polypeptide; splice variants.