Integrins and other adhesion receptors are essential components for outside-in and inside-out signaling through the cell membrane. The platelet glycoprotein IIb-IIIa (also known as fibrinogen receptor or integrin q&) is activated by platelet agonists, inhibited by cyclic-nucleotide-elevating agents, and is involved in the activation of protein tyrosine kinases including the 125-kDa focal adhesion kinase (~~1 2 5~~~) .However, the molecular details of glycoprotein IIb-IIIa regulation are not well understood. Here we report that in ADP-activated human platelets CAMP-and cGMPdependent protein-kinase-mediated phosphorylation of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) at Ser157 correlates well with glycoprotein IIb-IIIa inhibition. Human platelets contain similar concentrations of glycoprotein IIb-IIIa complexes (fibrinogen binding sites) and VASP. Using gel-filtered platelets, CAMP-elevating agents [e.g. prostaglandin E, and the forskolin analog 6-(3-dimethylaminopropionyl)forskolin (NKH 477)] caused VASP Ser157 phosphorylation and inhibited glycoprotein IIb-IIIa activation up to 70-100%. NO-generating, cGMP-elevating agents [e.g. 3-morpholinosydnonimine hydrochloride (SIN1) and sodium nitroprusside] stimulated VASP Ser157 phosphorylation and inhibited glycoprotein IIb-IIIa activation up to a maximal extent of 30-50%. The effects of CAMP-and cGMP-elevating agents on VASP phosphorylation and fibrinogen binding were reversible and could be mimicked by membrane-permeant selective activators of platelet CAMP-or cGMP-dependent protein kinase, respectively. Using threshold concentrations, the nitrovasodilator SIN 1 potentiated the effects of the forskolin analog NKH 477 with respect to inhibition of platelet aggregation, VASP phosphorylation and glycoprotein IIb-IIIa inhibition. It is proposed that the inhitition of glycoprotein IIb-IIIa induced by cyclic nucleotide involves CAMPand cGMP-dependent protein-kinase-mediated VASP phosphorylation at Ser157.Adhesion, activation and aggregation of platelets and platelet -vessel-wall interactions are tightly regulated under physiological conditions and often impaired in diseases including congenital hemorrhagic diseases, atherosclerosis, hypertension and diabetes 11, 21. Important components of this vascular cell -cell and cell -matrix interaction are integrins and other adhesion receptors [3 -81. The platelet glycoprotein IIb-IIIa ((xllbp3) is one of the best-studied integrins and represents the functional fibrinogen receptor which is absent or impaired in the hereditary disorder Glanzmann's thrombasthenia [l, 5-81. Activated platelets contain at their sur-
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