title: Platelet kainate receptor signaling promotes thrombosis by stimulating cyclooxygenase activation.
abstract: BACKGROUND
  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 alpha-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.
  
  
  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.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Sun
authors.forename: AnneMarie
authors.initials: A
authors.lastname: Swaim
authors.forename: Jesus Enrique
authors.initials: JE
authors.lastname: Herrera
authors.forename: Diane
authors.initials: D
authors.lastname: Becker
authors.forename: Lewis
authors.initials: L
authors.lastname: Becker
authors.forename: Kalyan
authors.initials: K
authors.lastname: Srivastava
authors.forename: Laura E
authors.initials: LE
authors.lastname: Thompson
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Shero
authors.forename: Alita
authors.initials: A
authors.lastname: Perez-Tamayo
authors.forename: Bhoom
authors.initials: B
authors.lastname: Suktitipat
authors.forename: Rasika
authors.initials: R
authors.lastname: Mathias
authors.forename: Anis
authors.initials: A
authors.lastname: Contractor
authors.forename: Nauder
authors.initials: N
authors.lastname: Faraday
authors.forename: Craig N
authors.initials: CN
authors.lastname: Morrell
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism*; D000097806:GluK2 Kainate Receptor
chemical_list: D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor
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