CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors? - PubMed (original) (raw)

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CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?

C S Walker et al. Br J Pharmacol. 2013 Dec.

Abstract

The neuropeptide calcitonin gene-related peptide (CGRP) is reported to play an important role in migraine. It is expressed throughout the trigeminovascular system. Antagonists targeting the CGRP receptor have been developed and have shown efficacy in clinical trials for migraine. However, no CGRP antagonist is yet approved for treating this condition. The molecular composition of the CGRP receptor is unusual because it comprises two subunits; one is a GPCR, the calcitonin receptor-like receptor (CLR). This associates with receptor activity-modifying protein (RAMP) 1 to yield a functional receptor for CGRP. However, RAMP1 also associates with the calcitonin receptor, creating a receptor for the related peptide amylin but this also has high affinity for CGRP. Other combinations of CLR or the calcitonin receptor with RAMPs can also generate receptors that are responsive to CGRP. CGRP potentially modulates an array of signal transduction pathways downstream of activation of these receptors, in a cell type-dependent manner. The physiological significance of these signalling processes remains unclear but may be a potential avenue for refining drug design. This complexity has prompted us to review the signalling and expression of CGRP and related receptors in the trigeminovascular system. This reveals that more than one CGRP responsive receptor may be expressed in key parts of this system and that further work is required to determine their contribution to CGRP physiology and pathophysiology.

Linked articles: This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7.

Keywords: Amylin; CGRP; G-protein coupled receptor; GPCR; calcitonin gene-related peptide; migraine; trigeminal ganglia; trigeminovascular system.

© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

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Figures

Figure 1

Figure 1

The calcitonin receptor family. The relative potency of CGRP compared to AM or amylin (Amy) is shown above a schematic representation of the appropriate receptor complex (Alexander et al.,; Qi et al.,; Udawela et al._,_2008). The different receptor components are described in the legend, beneath the receptors.

Figure 2

Figure 2

Overview of potential CGRP and CGRP-responsive receptor expression in the trigeminovascular system. A composite of two stylized TG neurons is shown innervating the cranial vasculature and the spinal trigeminal nucleus (Oliver et al.,; Tolcos et al., ; Lennerz et al.,; Eftekhari et al.,; Bower et al.,; Eftekhari and Edvinsson, ; Walker and Hay, 2011).

Figure 3

Figure 3

Proposed cranial CGRP-responsive receptor signalling in arteries. (A) In vascular smooth muscle cells the CGRP receptor activates a Gαs-coupled signalling cascade. (B) In endothelium, activation of the CGRP receptor or an AM receptor (RAMP shown in white) activates Gαs and subsequently increases NO production, which can then act on vascular smooth muscle cells. Full arrows represent well-defined interactions, dashed arrows represent poorly defined or multistep pathways.

Figure 4

Figure 4

Proposed CGRP-responsive receptor signalling in the trigeminal ganglia. (A) In trigeminal ganglia neurons the CGRP receptor activates a Gαs-coupled signalling cascade. (B) In satellite glia, activation of the CGRP receptor likely activates Gαs and subsequently increases NO production. Full arrows represent well-defined interactions. Dashed arrows represent poorly defined or multistep pathways.

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