Rapid nitric oxide-induced desensitization of the cGMP response is caused by increased activity of phosphodiesterase type 5 paralleled by phosphorylation of the enzyme

doi:10.1083/jcb.200107001

Published 15 October 2001. doi:10.1083/jcb.200107001

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© The Rockefeller University Press, 0021-9525/2001/10/271 $5.00
The Journal of Cell Biology, Volume 155, Number 2, October 15, 2001 271-278

Article

Rapid nitric oxide–induced desensitization of the cGMP response is caused by increased activity of phosphodiesterase type 5 paralleled by phosphorylation of the enzyme

Florian Mullershausen¹, Michael Russwurm¹, W. Joseph Thompson², Li Liu², Doris Koesling¹ and Andreas Friebe¹

¹ Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, D-44780 Bochum, Germany
² Cell Pathways, Inc., Horsham, PA 19044

Address correspondence to Doris Koesling, Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, Universitätssr. 150, D-44780 Bochum, Germany. Tel.: 49-234-3226827. Fax: 49-234-3214521. E-mail: doris.koesling{at}ruhr-uni-bochum.de

Most of the effects of the signaling molecule nitric oxide (NO)are mediated by cGMP, which is synthesized by soluble guanylylcyclase and degraded by phosphodiesterases. Here we show thatin platelets and aortic tissue, NO led to a biphasic responsecharacterized by a tremendous increase in cGMP (up to 100-fold)in less than 30 s and a rapid decline, reflecting the tightlycontrolled balance of guanylyl cyclase and phosphodiesteraseactivities. Inverse to the reported increase in sensitivitycaused by NO shortage, concentrating NO attenuated the cGMPresponse in a concentration-dependent manner. We found thatguanylyl cyclase remained fully activated during the entirecourse of the cGMP response; thus, desensitization was not dueto a switched off guanylyl cyclase. However, when intact plateletswere incubated with NO and then lysed, enhanced activity ofphosphodiesterase type 5 was detected in the cytosol. Furthermore,this increase in cGMP degradation is paralleled by the phosphorylationof phosphodiesterase type 5 at Ser-92. Thus, our data suggestthat NO-induced desensitization of the cGMP response is causedby the phosphorylation and subsequent activity increase of phosphodiesterasetype 5.

Key Words: phosphodiesterase; cGMP; NO-sensitive guanylyl cyclase; platelets; desensitization

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