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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3519-3526.)
© 1997 American Heart Association, Inc.

Articles

Thrombin-Induced Thromboxane Synthesis by Human Platelets

Properties of an Anion Binding Exosite I– Independent Receptor

Ruth Ann Henriksen; Gennady P. Samokhin; ; Paula B. Tracy

From the Section of Allergy, Asthma, and Immunology, Department of Medicine, East Carolina University, Greenville, NC (R.A.H., G.P.S.); and the Department of Biochemistry and Cell and Molecular Biology Program, University of Vermont, Burlington (P.B.T.).

Correspondence to Ruth Ann Henriksen, Section of Allergy, Asthma, and Immunology, Department of Medicine, East Carolina University, Greenville, NC 27858-4354. E-mail rhenriksen{at}brody.med.ecu.edu

Abstract These studies have examined the effects of thrombin-related agonists in stimulating thromboxane production by human platelets. The results presented show that (1) the maximal response elicited by thrombin receptor agonist peptide (TRAP) stimulation was 40% to 50% of that seen with thrombin or the thrombin mutant Thrombin Quick I; (2) pretreatment of platelets with prostaglandin E₁ or genistein resulted in differential inhibition of thromboxane production in response to TRAP compared with either enzyme agonist; (3) an antibody to the thrombin receptor cleavage site that inhibits increases in intracellular [Ca²⁺] only partially reduced thromboxane production in response to 5 nmol/L thrombin and 15 nmol/L Thrombin Quick I; (4) preincubation with 20 µmol/L TRAP resulted in desensitization to further stimulation by 100 µmol/L TRAP, but not by 100 nmol/L thrombin; and (5) the response to thrombin after TRAP desensitization was completely inhibited by the tyrosine kinase inhibitor genistein and was independent of an intracellular [Ca²⁺] flux. The cumulative results may be explained by the existence of two proteolytically activated receptors that result in thromboxane production in response to thrombin. One is the thrombin receptor/substrate, PAR-1. Stimulation through the second receptor/substrate depends on a genistein-sensitive step, is independent of an intracellular Ca²⁺ flux, and is initiated by a thrombin-activated receptor that does not depend on interaction with anion-binding exosite I, as previously indicated by the relative activity of Thrombin Quick I in stimulating platelet aggregation and thromboxane production. The proposed second thrombin receptor on platelets represents an additional member of the class of proteolytically activated receptors.

Key Words: thrombin • thromboxane • platelets • thrombin receptor

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