PMID- 16990611
OWN - NLM
STAT- MEDLINE
DCOM- 20070830
LR  - 20220318
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 109
IP  - 2
DP  - 2007 Jan 15
TI  - IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus 
      formation.
PG  - 552-9
AB  - 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.
FAU - Antl, Melanie
AU  - Antl M
AD  - Institut fur Pharmakologie und Toxikologie der Technischen Universitat Munchen, 
      Germany.
FAU - von Bruhl, Marie-Luise
AU  - von Bruhl ML
FAU - Eiglsperger, Christina
AU  - Eiglsperger C
FAU - Werner, Matthias
AU  - Werner M
FAU - Konrad, Ildiko
AU  - Konrad I
FAU - Kocher, Thomas
AU  - Kocher T
FAU - Wilm, Matthias
AU  - Wilm M
FAU - Hofmann, Franz
AU  - Hofmann F
FAU - Massberg, Steffen
AU  - Massberg S
FAU - Schlossmann, Jens
AU  - Schlossmann J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060921
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Enzyme Activators)
RN  - 0 (IRAG1 protein, human)
RN  - 0 (Inositol 1,4,5-Trisphosphate Receptors)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoproteins)
RN  - 0 (protein kinase modulator)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
RN  - H2D2X058MU (Cyclic GMP)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Cyclic GMP/*metabolism
MH  - Cyclic GMP-Dependent Protein Kinases/metabolism
MH  - Enzyme Activators/pharmacology
MH  - Humans
MH  - Inositol 1,4,5-Trisphosphate Receptors/metabolism
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Membrane Proteins/genetics/*physiology
MH  - Mice
MH  - Mice, Knockout
MH  - Multiprotein Complexes/metabolism
MH  - Nitric Oxide/*metabolism
MH  - Phosphoproteins/genetics/*physiology
MH  - Phosphorylation
MH  - Platelet Aggregation/drug effects/*physiology
MH  - Reference Values
MH  - Signal Transduction/drug effects/*physiology
MH  - Thrombosis/metabolism/*prevention & control
EDAT- 2006/09/23 09:00
MHDA- 2007/08/31 09:00
CRDT- 2006/09/23 09:00
PHST- 2006/09/23 09:00 [pubmed]
PHST- 2007/08/31 09:00 [medline]
PHST- 2006/09/23 09:00 [entrez]
AID - S0006-4971(20)52062-4 [pii]
AID - 10.1182/blood-2005-10-026294 [doi]
PST - ppublish
SO  - Blood. 2007 Jan 15;109(2):552-9. doi: 10.1182/blood-2005-10-026294. Epub 2006 Sep 
      21.