In vivo reconstitution of the negative feedback in nitric oxide/cGMP signaling: role of phosphodiesterase type 5 phosphorylation

Molecular Biology of the Cell
Florian MullershausenAndreas Friebe

Abstract

Most effects of the messenger molecule nitric oxide (NO) are mediated by cGMP, which is formed by NO-sensitive guanylyl cyclase (GC) and degraded by phosphodiesterases (PDEs). In platelets, NO elicits a spike-like cGMP response and causes a sustained desensitization. Both characteristics have been attributed to PDE5 activation caused by cGMP binding to its regulatory GAF domain. Activation is paralleled by phosphorylation whose precise function remains unknown. Here, we report reconstitution of all features of the NO-induced cGMP response in human embryonic kidney cells by coexpressing NO-sensitive GC and PDE5. The spike-like cGMP response was blunted when PDE5 phosphorylation was enhanced by additional overexpression of cGMP-dependent protein kinase. Analysis of PDE5 activation in vitro revealed a discrepancy between the cGMP concentrations required for activation (micromolar) and reversal of activation (nanomolar), indicating the conversion of a low-affinity state to a high-affinity state upon binding of cGMP. Phosphorylation even increased the high apparent affinity enabling PDE5 activation to persist at extremely low cGMP concentrations. Our data suggest that the spike-like shape and the desensitization of the cGMP response...Continue Reading

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Citations

Dec 8, 2010·Proceedings of the National Academy of Sciences of the United States of America·Andrew M BatchelorJohn Garthwaite
Jul 17, 2009·The Journal of Biological Chemistry·Edward J HalveyJohn Garthwaite
Oct 22, 2011·The Journal of Biological Chemistry·Katherine C WoodJohn Garthwaite
Dec 23, 2006·Clinical and Experimental Pharmacology & Physiology·Yue Xia JiaYong Fen Qi
Nov 22, 2013·PloS One·Johannes StegbauerEvanthia Mergia
Apr 22, 2014·Life Sciences·Nivedita Singh, Sanjukta Patra
Jul 9, 2010·Kidney International·Danny PolzinFranziska Theilig
Jun 15, 2013·British Journal of Pharmacology·Barbara LiesAndreas Friebe
Aug 12, 2010·British Journal of Pharmacology·Ronald JägerMichael Russwurm
Jun 21, 2015·Free Radical Biology & Medicine·Yue WangZhongbing Lu
May 17, 2005·Drug Discovery Today·Jens Schlossmann, Franz Hofmann
Dec 6, 2005·Journal of the Society for Gynecologic Investigation·Alessia BelmonteEmilio Piccione
Feb 25, 2018·Current Heart Failure Reports·Prabhjot SinghJaved Butler
Mar 3, 2006·Molecular Pharmacology·Florian MullershausenDoris Koesling
May 23, 2007·The Biochemical Journal·Michael RusswurmDoris Koesling
Jun 24, 2005·Blood·P Claire WilliamsValerie B O'Donnell

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