title: CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?
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.
  
  
  BACKGROUND
  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.
authors: School of Biological Sciences, University of Auckland, New Zealand; Centre for Brain Research, University of Auckland, Auckland, New Zealand.
authors: C S
authors: CS
authors: Walker
authors: D L
authors: DL
authors: Hay
mesh_terms: D053607:Adrenomedullin / Q000378:metabolism*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000627:therapeutic use; D002536:Cerebral Arteries / Q000294:innervation*; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D058262:Receptor Activity-Modifying Protein 1 / Q000378:metabolism; D018003:Receptors, Calcitonin / Q000378:metabolism; D058287:Receptors, Islet Amyloid Polypeptide / Q000378:metabolism*; D015398:Signal Transduction; D012668:Trigeminal Ganglion / Q000378:metabolism / Q000503:physiopathology; D014276:Trigeminal Nerve / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D014278:Trigeminal Nuclei / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D014279:Trigeminal Nucleus, Spinal / Q000378:metabolism / Q000503:physiopathology; D014664:Vasodilation
chemical_list: D002491:Central Nervous System Agents; D058262:Receptor Activity-Modifying Protein 1; D018003:Receptors, Calcitonin; D058287:Receptors, Islet Amyloid Polypeptide; D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide
keywords: Amylin; CGRP; G-protein coupled receptor; GPCR; calcitonin gene-related peptide; migraine; trigeminal ganglia; trigeminovascular system