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

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.