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Blood, 1 November 2004, Vol. 104, No. 9, pp. 2775-2782. Prepublished online as a Blood First Edition Paper on July 20, 2004; DOI 10.1182/blood-2004-03-1058. This Article Full Text (PDF) All Versions of this Article: 2004-03-1058v1 104/9/2775    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jensen, B. O Articles by Holmsen, H. Search for Related Content PubMed PubMed Citation Articles by Jensen, B. O Articles by Holmsen, H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 30, 2004 Accepted June 18, 2004 Protein Kinase A Mediates Inhibition of the Thrombin-induced Platelet Shape Change by Nitric Oxide Baard O Jensen, Frode Selheim, Stein O Doskeland, Adrian R Gear, and Holm Holmsen* Sections of Biochemistry and Molecular Biology, Department of Biomedicine, University of Bergen, Bergen, Norway Anatomy and Cell Biology, Department of Biochemistry and Molecular Genetics, University of Bergen, Bergen, Norway Department of Biochemistry and Molecular Genetics, University of Virginia Health Sciences Center, Charlottesville, VA, USA * Corresponding author; email: holm.holmsen{at}ibmb.uib.no. The thrombin-induced platelet shape change was blocked by nitric oxide (NO), as revealed by scanning electron microscopy, light transmission, and resistive-particle volume determination. The inhibitory effect of NO was accompanied by an increase in both cGMP- and cAMP-levels, and phosphorylation of the vasodilator-stimulated phosphoprotein (VASP). However, the inhibition of the shape change was only mimicked by cAMP analogs (Sp-5,6-DCl-cBIMPS, 8-AHA-cAMP and 8-CPT-cAMP), and not by cGMP analogs (8-Br-PET-cGMP, 8-Br-cGMP and 8-pCPT-cGMP). The effect of NO on the thrombin-induced shape change was prevented by the PKA-antagonists Rp-8-Br-cAMPS and Rp-cAMPS. The PKG-antagonist Rp-8-CPT-cGMPS strongly inhibited PKG-mediated 46 kDa VASP Ser239 phosphorylation, but did not inhibit the thrombin-induced shape change or the PKA-mediated VASP Ser157 phosphorylation. While an inhibitor of cyclic nucleotide phosphodiesterase (PDE)3A (milrinone) mimicked the effect of NO, inhibitors of PDE2 (erythro-9-(2-hydroxyl-3-nonyl)adenine) and PDE5 (dipyramidol) were poorly effective. We conclude that: 1) NO was a potent and reversible inhibitor of the platelet shape change, 2) the shape change was reversible, 3) the inhibitory effect of NO was mediated through activation of PKA, 4) the onset of the NO effect coincided with VASP Ser157 phosphorylation, 5) removal of NO and platelet shape change coincided with VASP Ser157 dephosphorylation. These findings are compatible with elevation of cGMP by NO in a compartment close to PDE3A, PKA and VASP, leading to a local increase of cAMP able to block thrombin-induced shape change. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Kuo The influence of methylmercury on the nitric oxide production of alveolar macrophages Toxicology and Industrial Health, September 1, 2008; 24(8): 531 - 538. [Abstract] [PDF] I. Russo, P. Del Mese, G. Doronzo, A. De Salve, M. Secchi, M. Trovati, and G. Anfossi Platelet Resistance to the Antiaggregatory Cyclic Nucleotides in Central Obesity Involves Reduced Phosphorylation of Vasodilator-Stimulated Phosphoprotein Clin. Chem., June 1, 2007; 53(6): 1053 - 1060. [Abstract] [Full Text] [PDF] F. Hofmann, R. Feil, T. Kleppisch, and J. Schlossmann Function of cGMP-Dependent Protein Kinases as Revealed by Gene Deletion Physiol Rev, January 1, 2006; 86(1): 1 - 23. [Abstract] [Full Text] [PDF]

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