CALCITONIN GENE-RELATED PEPTIDE: FROM MOLECULAR BIOLOGY AND RECEPTOR PHARMACOLOGY TO CLINICAL TARGETING IN MIGRAINE

Calcitonin gene-related peptide (CGRP) is a 37-residue neuropeptide generated by tissue-specific processing of the calcitonin gene transcript. It is stored in and released from sensory nerve endings, acts mainly at a receptor built from the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), and can also activate the AMY1 amylin receptor. Signalling is chiefly through Gs-coupled cyclic adenosine monophosphate (cAMP) formation, with additional G-protein and β-arrestin routes in some cells. These pathways allow CGRP to influence vascular tone, nociceptive transmission, neuro-immune communication, bone turnover, gut function and wound repair. Experimental provocation of migraine-like attacks by CGRP infusion established its causal role in migraine and led to four monoclonal antibodies (erenumab, fremanezumab, galcanezumab and eptinezumab) and four small-molecule receptor antagonists, the gepants (ubrogepant, rimegepant, atogepant and zavegepant). This review summarises gene and peptide biology, receptor pharmacology, intracellular signalling, organ-level functions, and the pharmacology, efficacy and safety of the approved CGRP-targeted drugs. It also discusses unresolved questions, including the consequences of long-term CGRP blockade, the contribution of non-canonical receptors, and the prospects for use outside migraine.