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¹ Department of Molecular and Comparative Pathobiology, ² Department of Medicine, ³ Department of Neuroscience, ⁴ Howard Hughes Medical Institute, ⁵ Department of Neurology, ⁶ Department of Anesthesia and Critical Care,and ⁷ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
⁸ Department of Veterinary Pharmacology, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan
⁹ Department of Physiology, Ege University School of Medicine, 35100 Izmir, Turkey
¹⁰ Max Planck Institute for Medical Research, Department of Molecular Neurobiology, D-69120, Heidelberg, Germany

CORRESPONDENCE Craig Morrell: cmorrell{at}jhmi.edu

Glutamate is an excitatory neurotransmitter that binds to the kainate receptor, the N-methyl-D-aspartate (NMDA) receptor, and the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR). Each receptor was first characterized and cloned in the central nervous system (CNS). Glutamate is also present in the periphery, and glutamate receptors have been identified in nonneuronal tissues, including bone, heart, kidney, pancreas, and platelets. Platelets play a central role in normal thrombosis and hemostasis, as well as contributing greatly to diseases such as stroke and myocardial infarction. Despite the presence of glutamate in platelet granules, the role of glutamate during hemostasis is unknown. We now show that activated platelets release glutamate, that platelets express AMPAR subunits, and that glutamate increases agonist-induced platelet activation. Furthermore, we demonstrate that glutamate binding to the AMPAR increases intracellular sodium concentration and depolarizes platelets, which are important steps in platelet activation. In contrast, platelets treated with the AMPAR antagonist CNQX or platelets derived from GluR1 knockout mice are resistant to AMPA effects. Importantly, mice lacking GluR1 have a prolonged time to thrombosis in vivo. Our data identify glutamate as a regulator of platelet activation, and suggest that the AMPA receptor is a novel antithrombotic target.

Abbreviations used: AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPAR, AMPA receptor; CNS, central nervous system; CPP, (±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; GPCR, G protein–coupled receptor; JST, Joro spider toxin; NHE, Na⁺/H⁺ exchanger; NMDA, N-methyl-D-aspartate; NMDAR, NMDA receptor; PRP, platelet-rich plasma; SBFI, sodium-binding benzofuran isophthalate; TRAP, thrombin receptor–activating peptide.

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