CGRP and its receptors

Abstract

The calcitonin gene-related peptide (CGRP) neuropeptide system is an important but still evolving target for migraine. A fundamental consideration for all of the current drugs in clinical trials and for ongoing development in this area is the identity, expression pattern, and function of CGRP receptors because this knowledge informs safety and efficacy considerations. In recent years, only the calcitonin receptor-like receptor/receptor activity-modifying protein 1 (RAMP1) complex, known as the CGRP receptor, has generally been considered relevant. However, CGRP is capable of activating multiple receptors and could have more than one endogenous receptor. The recent identification of the CGRP-responsive calcitonin receptor/RAMP1 complex (AMY receptor - amylin subtype 1 receptor) in the trigeminovascular system warrants a deeper consideration of the molecular identity of CGRP receptor(s) involved in the pathophysiology, and thus potential treatment of migraine. This perspective considers some of the issues and implications.

CGRP, Amylin, Immunology, and Headache Medicine

“…28 A CGRP receptor does not bind the amylin ligand to any significant degree, or at least without significant activity. After characterizing CGRP, the first CGRP receptor antagonist was developed, CGRP .…”

“…29 The receptor-binding regions of CGRP isoforms and amylin have high amino acid similarity, especially over their 5′ coding regions where all 3 peptides conserve posttranslational intramolecular disulfide bridge modifications. 28,33 βCGRP has a separate genetic origin and is encoded on chromosome 11p14.2-p12 by the calcitonin polypeptide beta (CALCB) gene. 29,31 It is, therefore, not surprising that CGRP isoforms and amylin share a receptor and are reported to have several similar biological actions.…”

Amylin

“…Critically, although these complexes are named amylin receptors because of their high affinity for this peptide, we do not know which of these receptors is responsible for mediating any given action of amylin in vivo . Moreover, some of these complexes (human and rodent AMY 1 receptors; rodent AMY 3 receptor) have high affinity for CGRP and could equally well mediate an endogenous action of CGRP, depending on if/when either of the peptides has access to these binding sites . The possible role of the AMY 1 receptor in CGRP biology has recently been reviewed .…”

“…Mutation of this residue in RAMP1 leads to a loss of antagonist affinity in both the CGRP receptor and AMY 1 receptor . The ‘gepants’ and related molecules with reported pharmacology all have higher affinity for the CGRP receptor than the AMY 1 receptor but this difference can approach only 10‐fold …”

“…Amylin is especially closely related to calcitonin gene‐related peptide (CGRP). CGRP and amylin are both 37 amino acids in length; 16 amino acids are identical between the two peptides . The N and C terminal regions of these peptides, which have important roles in receptor activation and affinity respectively, have especially high amino acid similarity .…”