Role of cyclic nucleotide-dependent protein kinases and their common substrate VASP in the regulation of human platelets.
The activation of human platelets is inhibited by two intracellular pathways regulated by either cGMP- or cAMP-elevating agents. There is considerable evidence that the inhibitory effects of cGMP and cAMP are mediated by the cGMP-PK and cAMP-PK, respectively, in human platelets. The cGI-PDE is an additional target for cGMP, and the cGMP-mediated elevation of cAMP levels contributes to the well known synergism between cAMP- and cGMP-elevating platelet inhibitors. Stimulation of both cAMP-PK and cGMP-PK prevents the agonist-induced activation of MLCK and PKC and inhibits the agonist-induced calcium mobilization from intracellular stores without any major effect on the ADP-regulated cation channel. These studies suggest that the inhibition of an early event of platelet activation, e.g. activation of PLC, is an effect common to both cGMP-PK and cAMP-PK stimulation. A common substrate of both cGMP-PK and cAMP-PK, the 46/50 kDa protein VASP, has been recently identified as a novel microfilament- and focal contact-associated protein whose phosphorylation correlates very well with platelet inhibition. Future investigations will have to identify the precise molecular mechanism of cyclic nucleotide inhibition of Ca2+ discharge from intracellular stores and whether cGMP-PK- and cAMP-PK-mediated VASP phosphorylation is an important component of this effect of cyclic nucleotides in human platelets.
Walter
U
U
Medizinische Universitätsklinik, Klinische Forschergruppe, Würzburg, Germany.
Eigenthaler
M
M
Geiger
J
J
Reinhard
M
M
D000262:Adenylyl Cyclases / Q000502:physiology; D001792:Blood Platelets / Q000201:enzymology; D002118:Calcium / Q000502:physiology; D015815:Cell Adhesion Molecules; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D008840:Microfilament Proteins; D009219:Myosin-Light-Chain Kinase / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D015539:Platelet Activation / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D009219:Myosin-Light-Chain Kinase; D000262:Adenylyl Cyclases; D006152:Cyclic GMP; D002118:Calcium