A PEPTIDE LIGAND OF THE HUMAN THROMBIN RECEPTOR ANTAGONIZES ALPHA-THROMBIN AND PARTIALLY ACTIVATES PLATELETS

The peptide YFLLRNP antagonizes the aggregation of human platelets whe n induced by low concentrations of alpha-thrombin or the thrombin rece ptor agonist peptide (SFLLRNP), demonstrating that it interacts specif ically with the thrombin receptor. Platelets exposed to YFLLRNP show i mmediate shape change (pseudopod formation) and potentiation of the AD P and platelet-activating factor response, but no Ca2+ mobilization, P 47 (pleckstrin) phosphorylation, secretion, or aggregation. Thus, YFLL RNP induces a state of partial activation of the platelets. Furthermor e, with platelets prestimulated with adrenalin (10 muM), YFLLRNP induc es aggregation, but no secretion, and only in the presence of added fi brinogen. We also found that prostacyclin inhibits the YFLLRNP-induced shape change; but EDTA, aspirin, and apyrase (ADP scavenger) do not. Thus, the thrombin receptor in platelets may communicate, independentl y of Ca2+ mobilization and P47 phosphorylation (protein kinase C activ ation), with intracellular signaling mechanisms that 1) modulate the c ytoskeleton structure, 2) potentiate other platelet responses, and 3) stimulate coupling between the thrombin receptor and fibrinogen bindin g (the glycoprotein IIb-IIIa complex). YFLLRNP may be useful for diffe rentiating between several possible activation states of the platelet thrombin receptor.