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.
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3 March 2003
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February 25 2003
Direct activation of PDE5 by cGMP : long-term effects within NO/cGMP signaling
Florian Mullershausen,
Florian Mullershausen
1Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany
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Andreas Friebe,
Andreas Friebe
1Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany
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Robert Feil,
Robert Feil
2Institut für Pharmakologie und Toxikologie der Technischen Universität München, 80802 München, Germany
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W. Joseph Thompson,
W. Joseph Thompson
3Department of Pharmacology, University of South Alabama School of Medicine, Mobile, AL 36688
4Cell Pathways, Inc., Horsham, PA 19044
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Franz Hofmann,
Franz Hofmann
2Institut für Pharmakologie und Toxikologie der Technischen Universität München, 80802 München, Germany
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Doris Koesling
Doris Koesling
1Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany
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Florian Mullershausen
1Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany
Andreas Friebe
1Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany
Robert Feil
2Institut für Pharmakologie und Toxikologie der Technischen Universität München, 80802 München, Germany
W. Joseph Thompson
3Department of Pharmacology, University of South Alabama School of Medicine, Mobile, AL 36688
4Cell Pathways, Inc., Horsham, PA 19044
Franz Hofmann
2Institut für Pharmakologie und Toxikologie der Technischen Universität München, 80802 München, Germany
Doris Koesling
1Abteilung für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany
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: [email protected]
*
Abbreviations used in this paper: cGKI, cyclic GMP-dependent protein kinase I; cAK, cyclic AMP-dependent protein kinase; NO, nitric oxide; ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; PDE, phosphodiesterase; VASP, vasodilator-activated stimulated phosphoprotein; WT, wild-type.
Received:
December 20 2002
Revision Received:
January 16 2003
Accepted:
January 21 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 160 (5): 719–727.
Article history
Received:
December 20 2002
Revision Received:
January 16 2003
Accepted:
January 21 2003
Citation
Florian Mullershausen, Andreas Friebe, Robert Feil, W. Joseph Thompson, Franz Hofmann, Doris Koesling; Direct activation of PDE5 by cGMP : long-term effects within NO/cGMP signaling . J Cell Biol 3 March 2003; 160 (5): 719–727. doi: https://doi.org/10.1083/jcb.200211041
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