Inhibition of platelet P2Y12 and alpha2A receptor signaling by cGMP-dependent protein kinase.
The important role of cGMP and cGMP-dependent protein kinase (cGPK) for the inhibition of platelet activation and aggregation is well established and due to the inhibition of fundamental platelet responses such as agonist-stimulated calcium increase, exposure of adhesion receptors and actin polymerization. The diversity of cGMP binding proteins and their synergistic interaction with cAMP signaling in inhibiting platelets indicates that a variety of cGMP targets contribute to its antiplatelet action. Since stimulation of G(i)-proteins was recently shown to be essential for complete platelet activation/aggregation, the possibility that G(i)-signaling events are cGMP/cGPK targets was investigated. Thus, the effect of elevated cGMP levels and selective cGPK activation on purinergic and adrenergic receptor-evoked decrease of platelet cAMP content was closely examined. Experiments with a selective activator of cGPK demonstrate for the first time a cGMP-caused G(i)-protein inhibition and our data suggest that this effect is mediated by cGPK. Considering the essential role of G(i)-signaling for platelet activation, we propose that inhibition of G(i)-mediated signaling by cGMP/cGPK is an important mechanism of action underlying the platelet inhibition by cGMP-elevating endothelium derived factors and drugs.
Aktas
Barsom
B
Institut für Klinische Biochemie und Pathobiochemie, Medizinische Universitätsklinik, Josef-Schneider Str. 2, D-97078, Würzburg, Germany.
Hönig-Liedl
Petra
P
Walter
Ulrich
U
Geiger
Jörg
J
D001792:Blood Platelets / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction / Q000502:physiology*
C547768:ADRA2A protein, human; D008565:Membrane Proteins; C548576:P2RY12 protein, human; D018341:Receptors, Adrenergic, alpha-2; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP