Contractile agonists attenuate cGMP levels by stimulating phosphorylation of cGMP-specific PDE5; an effect mediated by RhoA/PKC-dependent inhibition of protein phosphatase 1.

British Journal of Pharmacology
K S Murthy

Abstract

In gastrointestinal smooth muscle cGMP levels in response to relaxant agonists are regulated by PKG-mediated phosphorylation and activation of phosphodiesterase 5 (PDE5). The aim of the present study was to determine whether contractile agonists modulate cGMP levels by cross-regulating PDE5 activity and to identify the mechanism of action. Dispersed and cultured muscle cells from rabbit stomach were treated with the nitric oxide donor, S-nitrosoglutathione (GSNO), or with a contractile agonist, ACh and GSNO. PDE5 phosphorylation and activity, and cGMP levels were determined. GSNO stimulated PDE5 phosphorylation and activity and increased cGMP levels in gastric smooth muscle cells. Concurrent activation of cells with ACh augmented GSNO-stimulated PDE5 phosphorylation and activity, and attenuated cGMP levels. The effect of ACh was blocked by the m3 receptor antagonist and by inhibitors of protein kinase C (PKC) or RhoA, but not by the m2 receptor antagonist or inhibitors of PI hydrolysis. The effects of ACh on PDE5 phosphorylation and activity, and cGMP levels were mimicked by a low concentration of tautomycin (10 nM), and a high (1 microM) but not low (1 nM) concentration of okadaic acid. PDE5 was associated with protein phospha...Continue Reading

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Citations

Oct 23, 2012·American Journal of Physiology. Heart and Circulatory Physiology·Praveen ShuklaStephen T O'Rourke
Feb 3, 2016·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·H MiwaJ Watari
Jan 18, 2013·American Journal of Physiology. Cell Physiology·Trent ButlerEng-Cheng Chan
Oct 26, 2013·American Journal of Physiology. Gastrointestinal and Liver Physiology·Sunila MahavadiKarnam S Murthy
May 18, 2020·Chinese Journal of Integrative Medicine·Bin WangZhen Liu
Mar 17, 2009·The Journal of Sexual Medicine·Ching-Shwun Lin

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