Platelet Kainate Receptor Signaling Promotes Thrombosis by Stimulating Cyclooxygenase Activation

• Published in: Circulation research 2009-09, Vol.105 (6), p.595-603
• Main Authors: Sun, Henry, Swaim, AnneMarie, Herrera, Jesus Enrique, Becker, Diane, Becker, Lewis, Srivastava, Kalyan, Thompson, Laura E, Shero, Michelle R, Perez-Tamayo, Alita, Suktitipat, Bhoom, Mathias, Rasika, Contractor, Anis, Faraday, Nauder, Morrell, Craig N
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Platelets - metabolism; Excitatory Amino Acid Agonists - pharmacology; Fundamental and applied biological sciences. Psychology; GluK2 Kainate Receptor; Humans; Kainic Acid - pharmacology; Mice; Mice, Knockout; Platelet Activation; Prostaglandin-Endoperoxide Synthases - genetics; Prostaglandin-Endoperoxide Synthases - metabolism; Receptors, Kainic Acid - genetics; Receptors, Kainic Acid - metabolism; Thrombosis - genetics; Thrombosis - metabolism; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.198861

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.