Platelet Kainate Receptor Signaling Promotes Thrombosis by Stimulating Cyclooxygenase Activation

Author:

Sun Henry1,Swaim AnneMarie1,Herrera Jesus Enrique1,Becker Diane1,Becker Lewis1,Srivastava Kalyan1,Thompson Laura E.1,Shero Michelle R.1,Perez-Tamayo Alita1,Suktitipat Bhoom1,Mathias Rasika1,Contractor Anis1,Faraday Nauder1,Morrell Craig N.1

Affiliation:

1. 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.

Abstract

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 α-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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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