Inhibitory phosphorylation of soluble guanylyl cyclase by muscarinic m2 receptors via Gbetagamma-dependent activation of c-Src kinase

The Journal of Pharmacology and Experimental Therapeutics
K S Murthy

Abstract

In gastrointestinal smooth muscle, cGMP levels in response to relaxant agonists are regulated by activation of phosphodiesterase 5 and inhibition of soluble guanylyl cyclase (sGC) in a feedback mechanism via cGMP-dependent protein kinase. The aim of the present study was to determine whether contractile agonists modulate cGMP levels by cross-regulating sGC activity. In gastric muscle cells, acetylcholine (ACh) stimulated Src activity and induced sGC phosphorylation. Concurrent stimulation of cells with ACh attenuated sGC activity and cGMP formation in response to the nitric oxide (NO) donor, S-nitrosoglutathione (GSNO). The effect of ACh on Src activity, sGC phosphorylation, and on GSNO-stimulated sGC activity and cGMP formation were blocked by the m2 receptor antagonist (methoctramine), pertussis toxin, and by inhibitors of phosphatidylinositol 3 kinase, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], or Src kinase, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, in dispersed muscle cells and in cells expressing Galpha(i) minigene or Gbetagamma-scavenging peptide, whereas the m3 receptor antagonist, N-(2-chloroethyl)-4-piperidinyl diphenylacetate, or expression of the Galpha(q) mini...Continue Reading

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Citations

Oct 8, 2009·American Journal of Physiology. Gastrointestinal and Liver Physiology·Robert S FlynnJohn F Kuemmerle
Aug 7, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Allan T GulledgeHermes H Yeh
Apr 5, 2014·BioMed Research International·Natalie SampsonChristoph Zenzmaier
Nov 15, 2012·Oxidative Medicine and Cellular Longevity·Natalie SampsonChristoph Zenzmaier
Apr 29, 2014·Frontiers in Physiology·Natasha M RogersJeffrey S Isenberg
Jul 1, 2008·The European Journal of Neuroscience·John Garthwaite
Mar 1, 2014·American Journal of Physiology. Gastrointestinal and Liver Physiology·Jiean HuangKarnam S Murthy

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