CGRP Receptor Signalling Pathways

  • Graeme S. CottrellEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 255)


Calcitonin gene-related peptide (CGRP) is a promiscuous peptide, similar to many other members of the calcitonin family of peptides. The potential of CGRP to act on many different receptors with differing affinities and efficacies makes deciphering the signalling from the CGRP receptor a challenging task for researchers.

Although it is not a typical G protein-coupled receptor (GPCR), in that it is composed not just of a GPCR, the CGRP receptor activates many of the same signalling pathways common for other GPCRs. This includes the family of G proteins and a variety of protein kinases and transcription factors. It is now also clear that in addition to the initiation of cell-surface signalling, GPCRs, including the CGRP receptor, also activate distinct signalling pathways as the receptor is trafficking along the endocytic conduit.

Given CGRP’s characteristic of activating multiple GPCRs, we will first consider the complex of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) as the CGRP receptor. We will discuss the discovery of the CGRP receptor components, the molecular mechanisms controlling its internalization and post-endocytic trafficking (recycling and degradation) and the diverse signalling cascades that are elicited by this receptor in model cell lines. We will then discuss CGRP-mediated signalling pathways in primary cells pertinent to migraine including neurons, glial cells and vascular smooth muscle cells.

Investigation of all the CGRP- and CGRP receptor-mediated signalling cascades is vital if we are to fully understand CGRP’s role in migraine and will no doubt unearth new targets for the treatment of migraine and other CGRP-driven diseases.


Calcitonin gene-related peptide Calcitonin receptor-like receptor G protein Protein kinase Receptor activity-modifying protein Signalling Trafficking 



Adenosine triphosphate


Cyclic adenosine monophosphate


Calcitonin gene-related peptide


Calcitonin receptor-like receptor


Endothelin-converting enzyme 1


Extracellular-regulated protein kinase


Endothelin A receptor


G protein-coupled receptor




c-Jun N-terminal kinase


Protein kinase A


Protein kinase C


Nitric oxide


Nitric oxide synthase


Receptor activity-modifying protein


Receptor component protein


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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University of ReadingReadingUK

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