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Endosomal proteolysis regulates calcitonin gene‐related peptide responses in mesenteric arteries
Author(s) -
McNeish AJ,
Roux BT,
Aylett SB,
Van Den Brink AM,
Cottrell GS
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02129.x
Subject(s) - calcitonin gene related peptide , mesenteric arteries , medicine , endocrinology , vasodilation , vascular smooth muscle , calcitonin , electrical impedance myography , chemistry , receptor , neuropeptide , artery , smooth muscle
Background and Purpose Calcitonin gene‐related peptide ( CGRP ) is a potent vasodilator, implicated in the pathogenesis of migraine. CGRP activates a receptor complex comprising, calcitonin receptor‐like receptor ( CLR ) and receptor activity‐modifying protein 1 ( RAMP 1). In vitro studies indicate recycling of CLR ● RAMP 1 is regulated by degradation of CGRP in early endosomes by endothelin‐converting enzyme‐1 ( ECE ‐1). However, it is not known if ECE ‐1 regulates the resensitization of CGRP ‐induced responses in functional arterial tissue. Experimental Approach CLR , ECE ‐1a‐d and RAMP 1 expression in rat mesenteric artery smooth muscle cells ( RMA ‐ SMCs ) and mesenteric arteries was analysed by RT‐PCR and by immunofluorescence and confocal microscopy. CGRP ‐induced signalling in cells was examined by measuring cAMP production and ERK activation. CGRP ‐induced relaxation of arteries was measured by isometric wire myography. ECE ‐1 was inhibited using the specific inhibitor, SM ‐19712. Key Results RMA ‐ SMCs and arteries contained mRNA for CLR , ECE ‐1a‐d and RAMP 1. ECE ‐1 was present in early endosomes of RMA ‐ SMCs and in the smooth muscle layer of arteries. CGRP induced endothelium‐independent relaxation of arteries. ECE ‐1 inhibition had no effect on initial CGRP ‐induced responses but reduced cAMP generation in RMA ‐ SMCs and vasodilation in mesenteric arteries responses to subsequent CGRP challenges. Conclusions And Implications ECE ‐1 regulated the resensitization of responses to CGRP in RMA ‐ SMCs and mesenteric arteries. CGRP ‐induced relaxation did not involve endothelium‐derived pathways. This is the first report of ECE ‐1 regulating CGRP responses in SMCs and arteries. ECE ‐1 inhibitors may attenuate an important vasodilatory pathway, implicated in primary headaches and may represent a new therapeutic approach for the treatment of migraine.