Platelet kainate receptor signaling promotes thrombosis by stimulating cyclooxygenase activation.
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.
Sun
Henry
H
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Swaim
AnneMarie
A
Herrera
Jesus Enrique
JE
Becker
Diane
D
Becker
Lewis
L
Srivastava
Kalyan
K
Thompson
Laura E
LE
Shero
Michelle R
MR
Perez-Tamayo
Alita
A
Suktitipat
Bhoom
B
Mathias
Rasika
R
Contractor
Anis
A
Faraday
Nauder
N
Morrell
Craig N
CN
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
D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor
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