RGD Reference Report - Endosomal proteolysis regulates calcitonin gene-related peptide responses in mesenteric arteries. - Rat Genome Database

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Endosomal proteolysis regulates calcitonin gene-related peptide responses in mesenteric arteries.

Authors: McNeish, AJ  Roux, BT  Aylett, SB  Van Den Brink, AM  Cottrell, GS 
Citation: McNeish AJ, etal., Br J Pharmacol. 2012 Dec;167(8):1679-90. doi: 10.1111/j.1476-5381.2012.02129.x.
RGD ID: 7243859
Pubmed: PMID:22881710   (View Abstract at PubMed)
PMCID: PMC3525870   (View Article at PubMed Central)
DOI: DOI:10.1111/j.1476-5381.2012.02129.x   (Journal Full-text)

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 (RAMP1). In vitro studies indicate recycling of CLRRAMP1 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 RAMP1 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 RAMP1. 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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
blood vessel diameter maintenance  IMP 7243859 RGD 
positive regulation of cAMP-mediated signaling  IMP 7243859 RGD 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
early endosome  IDA 7243859 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ece1  (endothelin converting enzyme 1)


Additional Information