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Blood, 15 January 2007, Vol. 109, No. 2, pp. 552-559. Prepublished online as a Blood First Edition Paper on September 21, 2006; DOI 10.1182/blood-2005-10-026294. This Article Full Text (PDF) Supplemental Methods, Figures, and Videos All Versions of this Article: blood-2005-10-026294v1 109/2/552    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 Antl, M. Articles by Schlossmann, J. Search for Related Content PubMed PubMed Citation Articles by Antl, M. Articles by Schlossmann, J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 21, 2005 Accepted September 1, 2006 IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation Melanie Antl, Marie-Luise v. Bruhl, Christina Eiglsperger, Matthias Werner, Ildiko Konrad, Thomas Kocher, Matthias Wilm, Franz Hofmann, Steffen Massberg, and Jens Schlossmann* Institut fur Pharmakologie und Toxikologie, TU Munchen, Germany Deutsches Herzzentrum und 1. Medizinische Klinik, Klinikum rechts der Isar, TU Munchen, Germany Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT Biological & Medical Mass Spectrometry, Uppsala Biomedical Centrum, Uppsala, Sweden Protein and Peptide Group, EMBL, Heidelberg, Germany * Corresponding author; email: schlossmann{at}ipt.med.tu-muenchen.de. Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke.1 A central regulatory pathway conveying inhibition of platelet activation/aggregation is nitric oxide (NO)/cyclic GMP (cGMP) signaling via cGMP-dependent protein kinase I (cGKI).2,3 However, the regulatory cascade downstream of cGKI mediating platelet inhibition is still unclear. Here, we show that the inositol-1,4,5-trisphosphate receptor-associated cGMP kinase substrate (IRAG) is abundantly expressed in platelets and assembled in a macrocomplex together with cGKI and the inositol-1,4,5-trisphosphate receptor type I(InsP3RI). cGKI phosphorylates IRAG at Ser664 and Ser677 in intact platelets. Targeted deletion of the IRAG-InsP3RI interaction in IRAG12/12 mutant mice4 leads to a loss of NO/cGMP-dependent inhibition of fibrinogen-receptor activation and platelet aggregation. Intracellular calcium transients were not affected by DEA/NO or cGMP in mutant platelets. Furthermore, intravital microscopy shows that NO fails to prevent arterial thrombosis of the injured carotid artery in IRAG12/12 mutants. These findings reveal that interaction between IRAG and InsP3RI has a central role in NO/cGMP-dependent inhibition of platelet aggregation and in vivo thrombosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Tarin, M. Gomez, E. Calvo, J. A. Lopez, and C. Zaragoza Endothelial Nitric Oxide Deficiency Reduces MMP-13-Mediated Cleavage of ICAM-1 in Vascular Endothelium: A Role in Atherosclerosis Arterioscler Thromb Vasc Biol, January 1, 2009; 29(1): 27 - 32. [Abstract] [Full Text] [PDF] L. S. Wilson, H. S. Elbatarny, S. W. Crawley, B. M. Bennett, and D. H. Maurice Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions PNAS, September 9, 2008; 105(36): 13650 - 13655. [Abstract] [Full Text] [PDF] S. Weber, D. Bernhard, R. Lukowski, P. Weinmeister, R. Worner, J. W. Wegener, N. Valtcheva, S. Feil, J. Schlossmann, F. Hofmann, et al. Rescue of cGMP Kinase I Knockout Mice by Smooth Muscle Specific Expression of Either Isozyme Circ. Res., November 26, 2007; 101(11): 1096 - 1103. [Abstract] [Full Text] [PDF] M. L. Bilodeau and H. E. Hamm Regulation of Protease-Activated Receptor (PAR) 1 and PAR4 Signaling in Human Platelets by Compartmentalized Cyclic Nucleotide Actions J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 778 - 788. [Abstract] [Full Text] [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] C.-u. Choe and B. E. Ehrlich The Inositol 1,4,5-Trisphosphate Receptor (IP3R) and Its Regulators: Sometimes Good and Sometimes Bad Teamwork Sci. Signal., November 28, 2006; 2006(363): re15 - re15. [Abstract] [Full Text] [PDF]

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