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Published online 25 February 2003. doi:10.1083/jcb.200211041
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© The Rockefeller University Press, 0021-9525/2003/3/719 $5.00
The Journal of Cell Biology, Volume 160, Number 5, 719-727

Article

 Direct activation of PDE5 by cGMP : long-term effects within NO/cGMP signaling



Florian Mullershausen1, Andreas Friebe1, Robert Feil2, W. Joseph Thompson3,4, Franz Hofmann2 and Doris Koesling1

1 Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany
2 Institut für Pharmakologie und Toxikologie der Technischen Universität München, 80802 München, Germany
3 Department of Pharmacology, University of South Alabama School of Medicine, Mobile, AL 36688
4 Cell Pathways, Inc., Horsham, PA 19044

Address correspondence to Doris Koesling, Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, MA N1/43, Universitaetsstr. 150, 44780 Bochum, Germany. Tel.: 49-234-3226827. Fax: 49-234-3214521. E-mail: doris.koesling{at}ruhr-uni-bochum.de

In platelets, the nitric oxide (NO)–induced cGMP response is indicative of a highly regulated interplay of cGMP formation and cGMP degradation. Recently, we showed that within the NO-induced cGMP response in human platelets, activation and phosphorylation of phosphodiesterase type 5 (PDE5) occurred. Here, we identify cyclic GMP-dependent protein kinase I as the kinase responsible for the NO-induced PDE5 phosphorylation. However, we demonstrate that cGMP can directly activate PDE5 without phosphorylation in platelet cytosol, most likely via binding to the regulatory GAF domains. The reversal of activation was slow, and was not completed after 60 min. Phosphorylation enhanced the cGMP-induced activation, allowing it to occur at lower cGMP concentrations. Also, in intact platelets, a sustained NO-induced activation of PDE5 for as long as 60 min was detected. Finally, the long-term desensitization of the cGMP response induced by a low NO concentration reveals the physiological relevance of the PDE5 activation within NO/cGMP signaling. In sum, we suggest NO-induced activation and phosphorylation of PDE5 as the mechanism for a long-lasting negative feedback loop shaping the cGMP response in human platelets in order to adapt to the amount of NO available.

Key Words: cyclic GMP; cGMP-dependent protein kinase; GAF domain; guanylyl cyclase; platelets


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