Calcitonin Gene Related Peptide

CALCITONIN GENE RELATED PEPTIDE

Calcitonin gene-related peptide (CGRP) is a member of the calci-tonin family of peptides, which also includes calcitonin, adreno-medullin , and amylin. CGRP consists of 37 amino acids. Like calcitonin, CGRP is present in large quantities in the C cells of the thyroid gland. It is also distributed widely in the central and peripheral nervous systems, cardiovascular and respira-tory systems, and gastrointestinal tract. In the cardiovascular sys-tem CGRP-containing fibers are more abundant around arteries than around veins, and in atria than in ventricles. CGRP fibers are associated with most smooth muscles of the gastrointestinal tract. CGRP is found with substance P (see above) in some of these regions and with acetylcholine in others.

When CGRP is injected into the central nervous system, it produces a variety of effects, including hypertension and sup-pression of feeding. When injected into the systemic circula-tion, the peptide causes hypotension and tachycardia. The hypotensive action of CGRP results from the potent vasodila-tor action of the peptide; indeed, CGRP is the most potent vasodilator yet discovered. It dilates multiple vascular beds, but the coronary circulation is particularly sensitive. The vasodila-tion is mediated via a nonendothelial mechanism through activation of adenylyl cyclase.

Although CGRP receptors have traditionally been divided into two classes, CGRP₁ and CGRP₂, it now seems likely that the actions of CGRP are mediated by a single receptor. Specifically, the seven-transmembrane G protein-coupled calcitonin-like pro-tein receptor (CLR) co-assembles with the receptor activity-modifying protein RAMP1 to form a functional single CGRP receptor that can activate both G_s and G_q. Peptide and nonpeptide antagonists of the receptor have been developed. CGRP_8-37 has been used extensively to investigate the actions of CGRP but displays affinity for related receptors including those for adrenomedullin . Nonpeptide CGRP receptor antagonists target the inter-face between CLR and RAMP1 and thereby make them more selective for the CGRP receptor. These antagonists display species selectivity and are more selective for human than rodent receptors. Examples are olcegepant and telcagepant.

Evidence is accumulating that release of CGRP from trigemi-nal nerves plays a central role in the pathophysiology of migraine. The peptide is released during migraine attacks, and successful treatment of migraine with a selective serotonin agonist normal-izes cranial CGRP levels. Clinical trials with olcegepant and tel-cagepant have demonstrated that CGRP antagonism is an effective, well-tolerated treatment for migraine.