Signaling via IRAG is essential for NO/cGMP-dependent inhibition of platelet activation.
Platelet activation is strongly affected by nitric oxide/cyclic GMP (NO/cGMP) signaling involving cGMP-dependent protein kinase I (cGKI). Previously it was shown that interaction of the cGKI substrate IRAG with InsP(3)RI is essential for NO/cguanosine monophosphate (GMP)-dependent inhibition of platelet aggregation in vitro and in vivo. However, the role of Inositol-trisphosphate receptor associated cGMP kinase substrate (IRAG) for platelet adhesion or granule secretion was unknown. Here, we analysed the functional role of IRAG for platelet activation. Murine IRAG-deficient platelets displayed enhanced aggregability towards several agonists (collagen, thrombin and TxA2). NO- or cGMP-dependent inhibition of agonist induced ATP- or 5-HT secretion from dense granules, and P-selectin secretion from alpha granules was severely affected in IRAG-deficient platelets. Concomitantly, the effect of NO/cGMP on platelet aggregation was strongly reduced in IRAG-deficient platelets. Furthermore, GPIIb/IIIa-mediated adhesion of platelets to fibrinogen could only weakly be inhibited in IRAG-deficient mice contrary to wild-type (WT) mice. Our results suggest that signaling via IRAG is essential for NO/cGMP-dependent inhibition of platelet activation regarding granule secretion, aggregation and adhesion. This platelet disorder might cause that the bleeding time of IRAG-deficient mice was reduced.
Pharmacology and Toxicology, University Regensburg, Universitätsstr. 31, 93040 Regensburg, Germany.
Elisabeth
E
Schinner
Katharina
K
Salb
Jens
J
Schlossmann
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism*; D006152:Cyclic GMP / Q000097:blood*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000097:blood; D020536:Enzyme Activators / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000097:blood*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000097:blood*; D010750:Phosphoproteins / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D015539:Platelet Activation / Q000502:physiology*; D015398:Signal Transduction
D020536:Enzyme Activators; C485784:IRAG1 protein, human; D008565:Membrane Proteins; C485785:Mrvi1 protein, mouse; D010750:Phosphoproteins; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP