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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2007-1-9
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pubmed:abstractText |
Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke. A central regulatory pathway conveying inhibition of platelet activation/aggregation is nitric oxide (NO)/cyclic GMP (cGMP) signaling by cGMP-dependent protein kinase I (cGKI). 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 cGKIbeta 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 IRAGDelta12/Delta12 mutant mice 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 IRAGDelta12/Delta12 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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic GMP,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic GMP-Dependent Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Inositol 1,4,5-Trisphosphate...,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/MRVI1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Multiprotein Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/protein kinase modulator
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0006-4971
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
109
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
552-9
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:16990611-Animals,
pubmed-meshheading:16990611-Calcium,
pubmed-meshheading:16990611-Cyclic GMP,
pubmed-meshheading:16990611-Cyclic GMP-Dependent Protein Kinases,
pubmed-meshheading:16990611-Enzyme Activators,
pubmed-meshheading:16990611-Humans,
pubmed-meshheading:16990611-Inositol 1,4,5-Trisphosphate Receptors,
pubmed-meshheading:16990611-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:16990611-Membrane Proteins,
pubmed-meshheading:16990611-Mice,
pubmed-meshheading:16990611-Mice, Knockout,
pubmed-meshheading:16990611-Multiprotein Complexes,
pubmed-meshheading:16990611-Nitric Oxide,
pubmed-meshheading:16990611-Phosphoproteins,
pubmed-meshheading:16990611-Phosphorylation,
pubmed-meshheading:16990611-Platelet Aggregation,
pubmed-meshheading:16990611-Reference Values,
pubmed-meshheading:16990611-Signal Transduction,
pubmed-meshheading:16990611-Thrombosis
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pubmed:year |
2007
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pubmed:articleTitle |
IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation.
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pubmed:affiliation |
Institut für Pharmakologie und Toxikologie der Technischen Universität München, Germany.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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