A second trigeminal CGRP receptor: function and expression of the AMY1 receptor

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Abstract

Objective

The trigeminovascular system plays a central role in migraine, a condition in need of new treatments. The neuropeptide, calcitonin gene-related peptide (CGRP), is proposed as causative in migraine and is the subject of intensive drug discovery efforts. This study explores the expression and functionality of two CGRP receptor candidates in the sensory trigeminal system.

Methods

Receptor expression was determined using Taqman G protein-coupled receptor arrays and immunohistochemistry in trigeminal ganglia (TG) and the spinal trigeminal complex of the brainstem in rat and human. Receptor pharmacology was quantified using sensitive signaling assays in primary rat TG neurons.

Results

mRNA and histological expression analysis in rat and human samples revealed the presence of two CGRP-responsive receptors (AMY ₁: calcitonin receptor/receptor activity-modifying protein 1 [RAMP1]) and the CGRP receptor (calcitonin receptor-like receptor/RAMP1). In support of this finding, quantification of agonist and antagonist potencies revealed a dual population of functional CGRP-responsive receptors in primary rat TG neurons.

Interpretation

The unexpected presence of a functional non-canonical CGRP receptor (AMY ₁) at neural sites important for craniofacial pain has important implications for targeting the CGRP axis in migraine.

Related collections

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This study, which is a part of the initiative 'Lifting The Burden: The Global Campaign to Reduce the Burden of Headache Worldwide', assesses and presents all existing evidence of the world prevalence and burden of headache disorders. Population-based studies applying International Headache Society criteria for migraine and tension-type headache, and also studies on headache in general and 'chronic daily headache', have been included. Globally, the percentages of the adult population with an active headache disorder are 46% for headache in general, 11% for migraine, 42% for tension-type headache and 3% for chronic daily headache. Our calculations indicate that the disability attributable to tension-type headache is larger worldwide than that due to migraine. On the World Health Organization's ranking of causes of disability, this would bring headache disorders into the 10 most disabling conditions for the two genders, and into the five most disabling for women.

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Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial.

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Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered humanised anti-CGRP antibody, for migraine prevention.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Clin Transl Neurol

Journal ID (iso-abbrev): Ann Clin Transl Neurol

Journal ID (publisher-id): acn3

Title: Annals of Clinical and Translational Neurology

Publisher: John Wiley & Sons, Ltd (Chichester, UK )

ISSN (Print): 2328-9503

ISSN (Electronic): 2328-9503

Publication date (Print): June 2015

Publication date (Electronic): 01 April 2015

Volume: 2

Issue: 6

Pages: 595-608

Affiliations

[1 ]School of Biological Sciences, University of Auckland Auckland, 1142, New Zealand

[2 ]Centre for Brain Research, University of Auckland Auckland, 1142, New Zealand

[3 ]Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University Lund, Sweden

[4 ]Departments of Pharmacology and Medicine, University of California at San Diego La Jolla, California

[5 ]Department of Anatomy with Radiology, Faculty of Medical and Health Science, University of Auckland Auckland, 1142, New Zealand

[6 ]Department of Molecular Physiology and Biophysics, University of Iowa Iowa City, Iowa

[7 ]Department of Neurology, Veterans Affairs Medical Center, University of Iowa Iowa City, Iowa

Author notes

Correspondence Debbie L. Hay, School of Biological Sciences, 3A Symonds Street, University of Auckland, Auckland 1010, New Zealand. Tel and Fax: +64 9 373 7599; E-mail: dl.hay@ 123456auckland.ac.nz

Funding Information This work was supported by a grant from the Auckland Medical Research Foundation (to C. S. W. and D. L. H.), by the University of Auckland Biopharma Thematic Research Initiative (to D. L. H.), by the National Institutes of Health (to A. F. R.; NS075599), by the Swedish Research Council (to L. E.; grant no. 5958).

Article

DOI: 10.1002/acn3.197

PMC ID: 4479521

PubMed ID: 26125036

SO-VID: 467f3474-ec27-4b99-a3f4-0666d8147b06

License:

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 30 November 2014

Date revision received : 01 March 2015

Date accepted : 02 March 2015

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