Signaling via IRAG is essential for NO/cGMP-dependent inhibition of platelet activation

Platelets. 2011;22(3):217-27. doi: 10.3109/09537104.2010.544151. Epub 2011 Jan 18.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Platelets / enzymology
  • Blood Platelets / metabolism*
  • Cyclic GMP / blood*
  • Cyclic GMP-Dependent Protein Kinases / blood
  • Enzyme Activators / pharmacology
  • Humans
  • Membrane Proteins / blood*
  • Mice
  • Mice, Knockout
  • Nitric Oxide / blood*
  • Phosphoproteins / blood*
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Platelet Activation / physiology*
  • Signal Transduction

Substances

  • Enzyme Activators
  • IRAG1 protein, human
  • Membrane Proteins
  • Mrvi1 protein, mouse
  • Phosphoproteins
  • Nitric Oxide
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic GMP