G-protein ?? subunits in vasorelaxing and anti-endothelinergic effects of calcitonin gene-related peptide.

ABSTRACT:

Background and purpose

Calcitonin gene-related peptide (CGRP) has been proposed to relax vascular smooth muscle cells (VSMC) via cAMP and can promote dissociation of endothelin-1 (ET-1) from ET(A) receptors. The latter is not mimicked by other stimuli of adenylate cyclases. Therefore, we evaluated the involvement of G-protein ?? subunits (G??) in the arterial effects of CGRP receptor stimulation.

Experimental approach

To test the hypothesis that instead of ? subunits of G-proteins (G?s), G?? mediates the effects of CGRP receptor activation, we used (i) rat isolated mesenteric resistance arteries (MRA), (ii) pharmacological modulators of cyclic nucleotides; and (iii) low molecular weight inhibitors of the functions of G??, gallein and M119. To validate these tools with respect to CGRP receptor function, we performed organ bath studies with rat isolated MRA, radioligand binding on membranes from CHO cells expressing human CGRP receptors and cAMP production assays in rat cultured VSMC.

Key results

In isolated arteries contracted with K(+) or ET-1, IBMX (PDE inhibitor) increased sodium nitroprusside (SNP)- and isoprenaline (ISO)- but not CGRP-induced relaxations. While fluorescein (negative control) was without effects, gallein increased binding of [(125) I]-CGRP in the absence and presence of GTP?S. Gallein also increased CGRP-induced cAMP production in VSMC. Despite these stimulating effects, gallein and M119 selectively inhibited the relaxing and anti-endothelinergic effects of CGRP in isolated arteries while not altering contractile responses to K(+) or ET-1 or relaxing responses to ISO or SNP.

Conclusion and implications

Activated CGRP receptors induce cyclic nucleotide-independent relaxation of VSMC and terminate arterial effects of ET-1 via G??.

SUBMITTER: Meens MJ 

PROVIDER: S-EPMC3415655 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature