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).