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(Circulation Research. 2009;105:595.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Platelet Kainate Receptor Signaling Promotes Thrombosis by Stimulating Cyclooxygenase Activation

Henry Sun, AnneMarie Swaim, Jesus Enrique Herrera, Diane Becker, Lewis Becker, Kalyan Srivastava, Laura E. Thompson, Michelle R. Shero, Alita Perez-Tamayo, Bhoom Suktitipat, Rasika Mathias, Anis Contractor, Nauder Faraday, Craig N. Morrell

From the Departments of Medicine (H.S., H.E.H., D.B., L.B., B.S., R.M.), Molecular and Comparative Pathobiology (A.S., K.S., L.E.T., M.R.S., A.P.-T., C.N.M.), and Anesthesiology and Critical Care (N.F.), Johns Hopkins University School of Medicine, Baltimore, Md; and the Department of Physiology (A.C.), Northwestern University School of Medicine, Chicago, Ill. Current affiliation for K.S. and C.N.M.: Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry, NY.

Correspondence to Craig Morrell, Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry, 601 Elmwood Avenue, Box CVRI, Rochester, New York 14642. E-mail craig_morrell{at}urmc.rochester.edu

Rationale: Glutamate is a major signaling molecule that binds to glutamate receptors including the ionotropic glutamate receptors; kainate (KA) receptor (KAR), the N-methyl-D-aspartate receptor, and the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Each is well characterized in the central nervous system, but glutamate has important signaling roles in peripheral tissues as well, including a role in regulating platelet function.

Objective: Our previous work has demonstrated that glutamate is released by platelets in high concentrations within a developing thrombus and increases platelet activation and thrombosis. We now show that platelets express a functional KAR that drives increased agonist induced platelet activation.

Methods and Results: KAR induced increase in platelet activation is in part the result of activation of platelet cyclooxygenase in a mitogen-activated protein kinase–dependent manner. Platelets derived from KAR subunit knockout mice (GluR6^–/–) are resistant to KA effects and have a prolonged time to thrombosis in vivo. Importantly, we have also identified polymorphisms in KAR subunits that are associated with phenotypic changes in platelet function in a large group of whites and blacks.

Conclusions: Our data demonstrate that glutamate regulation of platelet activation is in part cyclooxygenase-dependent and suggest that the KAR is a novel antithrombotic target.

Key Words: platelet • kainate • glutamate • thrombosis • cyclooxygenase • thromboxane • mitogen activated kinase • p38