Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins

Abstract

Receptor activity-modifying proteins (RAMPs) are single pass membrane proteins initially identified by their ability to determine the pharmacology of the calcitonin receptor-like receptor (CLR), a family B G protein-coupled receptor (GPCR). It is now known that RAMPs can interact with a much wider range of GPCRs. This review considers recent developments on the structure of the complexes formed between the extracellular domains (ECDs) of CLR and RAMP1 or RAMP2 as these provide insights as to how the RAMPs direct ligand binding. The range of RAMP interactions is also considered; RAMPs can interact with numerous family B GPCRs as well as examples of family A and family C GPCRs. They influence receptor expression at the cell surface, trafficking, ligand binding and G protein coupling. The GPCR-RAMP interface offers opportunities for drug targeting, illustrated by examples of drugs developed for migraine.

Pituitary adenylate cyclase‐activating polypeptide receptors in the trigeminovascular system: implications for migraine

“…However, both the VPAC 1 and VPAC 2 receptor have been shown to interact with single‐transmembrane spanning receptor activity‐modifying proteins (RAMPs) (Christopoulos et al, ; Muller et al, ; Wootten et al, ). Three RAMPs have been identified, RAMP1, RAMP2 and RAMP3, which have been shown to interact with a subset of GPCRs (McLatchie et al, ; Hay et al, ; Hay and Pioszak, ). The formation of a heterodimer between a RAMP and a GPCR can result in altered ligand binding, receptor trafficking and/or intracellular signalling (Hay et al, ).…”

“…Three RAMPs have been identified, RAMP1, RAMP2 and RAMP3, which have been shown to interact with a subset of GPCRs (McLatchie et al, ; Hay et al, ; Hay and Pioszak, ). The formation of a heterodimer between a RAMP and a GPCR can result in altered ligand binding, receptor trafficking and/or intracellular signalling (Hay et al, ). In the case of VPAC 1 and VPAC 2 , co‐expression with RAMP1, 2 or 3 may result in altered G protein‐coupling and subsequent changes to downstream signalling events (Christopoulos et al, ; Wootten et al, ).…”

Structural Biology of Calcitonin: From Aqueous Therapeutic Properties to Amyloid Aggregation

“…The related amyloidogenic peptides CGRP and hIAPP have demonstrated an ability to activate CTR‐mediated inhibitory pathways in osteoclasts, although their interaction and subsequent inhibition is far weaker than the native substrate CT . The relative affinity of the CTR for different members of the calcitonin family is mediated by receptor activity modifying proteins (RAMPs), and as such, elucidating the behavior of RAMPs is the subject of significant scientific effort ,,…”

Calcitonin Gene‐Related Peptide Modulators – The History and Renaissance of a New Migraine Drug Class

“…In this model, the C‐terminal region of CGRP first binds with high affinity to the extracellular N‐terminal regions of CLR and RAMP1 forming an affinity trap that increases the local concentrations of CGRP to allow the N‐terminal of CGRP to interact with the juxta‐membrane region of CLR and trigger the accumulation of cAMP. The binding of CGRP to the AMY1 receptor (CTR + RAMP1) is thought to be a similar affinity trap mechanism due to the contribution of a common set of amino acids shared between CLR and CTR together with a common interaction with RAMP1 residue tryptophan 84 …”

“…The binding of CGRP to the AMY1 receptor (CTR + RAMP1) is thought to be a similar affinity trap mechanism due to the contribution of a common set of amino acids shared between CLR and CTR together with a common interaction with RAMP1 residue tryptophan 84. 9,[12][13][14][15] The role of CGRP in the pathogenesis of migraine and its history as an antimigraine drug target have been reviewed recently. 16 CGRP containing sensory nerve fibers and CGRP receptors are widely distributed peripherally and centrally throughout the trigeminovascular system, where they play an important role in its sensory physiology and pharmacology.…”