title: Glutamate mediates platelet activation through the AMPA receptor.
abstract: Glutamate is an excitatory neurotransmitter that binds to the kainate receptor, the N-methyl-D-aspartate (NMDA) receptor, and the alpha-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.
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. cmorrell@jhmi.edu
authors.forename: Craig N
authors.initials: CN
authors.lastname: Morrell
authors.forename: Henry
authors.initials: H
authors.lastname: Sun
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikeda
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beique
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Swaim
authors.forename: Emily
authors.initials: E
authors.lastname: Mason
authors.forename: Tanika V
authors.initials: TV
authors.lastname: Martin
authors.forename: Laura E
authors.initials: LE
authors.lastname: Thompson
authors.forename: Oguz
authors.initials: O
authors.lastname: Gozen
authors.forename: David
authors.initials: D
authors.lastname: Ampagoomian
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rothstein
authors.forename: Nauder
authors.initials: N
authors.lastname: Faraday
authors.forename: Richard
authors.initials: R
authors.lastname: Huganir
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lowenstein
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000097:blood* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D017136:Ion Transport; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000097:blood; D016194:Receptors, N-Methyl-D-Aspartate / Q000097:blood; D015398:Signal Transduction; D012964:Sodium / Q000097:blood; D013927:Thrombosis / Q000097:blood; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000097:blood / Q000494:pharmacology
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018698:Glutamic Acid; D007608:Kainic Acid; D018091:Receptors, AMPA; D043562:Receptors, G-Protein-Coupled; D016194:Receptors, N-Methyl-D-Aspartate; D012964:Sodium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid