Platelet kainate receptor signaling promotes thrombosis by stimulating cyclooxygenase activation

Henry Sun, Anne Marie Swaim, Jesus Enrique Herrera, Diane Becker, Lewis Becker, Kalyan Srivastava, Laura E. Thompson, Michelle R. Shero, Alita Perez-Tamayo, Bhoom Suktitipat, Rasika Mathias, Anis Contractor, Nauder Faraday, Craig N. Morrell

Research output: Contribution to journalArticle

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 cyclooxygenasedependent and suggest that the KAR is a novel antithrombotic target.

Original languageEnglish (US)
Pages (from-to)595-603
Number of pages9
JournalCirculation research
Volume105
Issue number6
DOIs
StatePublished - Dec 1 2009

Keywords

  • Cyclooxygenase
  • Glutamate
  • Kainate
  • Mitogen activated kinase
  • P38
  • Platelet
  • Thrombosis
  • Thromboxane

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Sun, H., Swaim, A. M., Herrera, J. E., Becker, D., Becker, L., Srivastava, K., Thompson, L. E., Shero, M. R., Perez-Tamayo, A., Suktitipat, B., Mathias, R., Contractor, A., Faraday, N., & Morrell, C. N. (2009). Platelet kainate receptor signaling promotes thrombosis by stimulating cyclooxygenase activation. Circulation research, 105(6), 595-603. https://doi.org/10.1161/CIRCRESAHA.109.198861