CGRP family; peptides and receptors.
The CGRP family of peptides (α and β forms) are ligands for a closely related family of G protein-coupled receptors (GPCRs) with shared structural homology (Hay et al., 2014). The CGRP family of peptides and receptors show a varying degree of structural homology with CGRP and have a widespread distribution throughout the body (Hendrikse, Bower, Hay & Walker, 2018).
The receptors in this group are formed from either of two 7-transmembrane (TM) G-protein coupled receptors (GPCRs), the calcitonin receptor-like receptor (CLR) or the calcitonin receptor (CTR), which interact with receptor activity-modifying protein (RAMPs) to form heterodimers (Gingell, Hendrikse & Hay, 2019). The RAMPs are a small family of three proteins (RAMP 1-3) that are single TM-spanning proteins that can modify binding characteristics, pharmacology, functionality and cell trafficking of the specific GPCRs (Hay & Pioszak, 2016). The currently most central is the 7-TM complex – CLR – which is a required element of receptors for CGRP and adrenomedullin (AM1and AM2). Early studies showed that transfecting cells with only CLR revealed no response to CGRP (McLatchie et al., 1998). It was only after the demonstration that the dimerization of RAMP1 and CLR resulted in formation of a functional receptor to CGRP (Hay, Garelja, Poyner & Walker, 2018). When CLR couples to RAMP2 or RAMP3 it forms AM1 receptor (CLR/RAMP2) or AM2 receptor (CLR/RAMP3). The AMY receptors are formed by association of the Calcitonin (CT) receptor (CTR) with a RAMP: AMY1receptor (CTR/RAMP1), AMY3 receptor (CTR/RAMP3). The CTR can also signal on its own, as a calcitonin receptor (without any RAMP) (Poyner et al., 2002). Due to the complexity of this peptide-receptor system, their expression in the trigeminal system is unclear and their functional roles yet to be resolved (Edvinsson, Grell & Warfvinge, 2020).