Physiology Glutamate at the Clot

L. Bryan Ray

Science, Science Signaling, AAAS, Washington, DC 20005, USA

Glutamate is best known as a neurotransmitter, but glutamate is also present in the blood, and various glutamate receptors are found in tissues that include pancreatic β cells and bone cells. Morrell et al. add an important new target for glutamate regulation--platelets. Platelets store glutamate and have glutamate transporters, and Morrell et al. used a real-time enzymatic assay to show that glutamate was released during aggregation of human platelets induced in vitro with thrombin. Immunoblotting showed that platelets express AMPA (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. Glutamate alone did not cause platelet activation, but it did enhance activation in response to thrombin receptor-activating peptide (TRAP-6), and pharmacological studies indicated that glutamate acted through AMPA receptors. The authors used studies with Na⁺-sensitive dye and electrophysiological experiments to determine that AMPA receptor activation increased Na⁺ influx and promoted depolarization of the plasma membrane. Platelets respond to many regulators, and AMPA receptor activation enhanced the response of platelets to agonists that act through heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. The authors also provided evidence from intravital microscopy to show that platelets from mice lacking the GluR1 subunit of the AMPA receptor had delayed thrombosis of experimentally damaged mesenteric arteries in vivo. Occlusion of arteries by thrombosis is a key mechanism in the deadly effects of cardiovascular disease and stroke. Thus, the authors suggest that AMPA receptors might provide a valuable new target for therapeutic inhibition of thrombosis.

C. N. Morrell, H. Sun, M. Ikeda, J.-C. Beique, A. M. Swaim, E. Mason, T. V. Martin, L. E. Thompson, O. Gozen, D. Ampagoomian, R. Sprengel, J. Rothstein, N. Faraday, R. Huganir, C. J. Lowenstein, Glutamate mediates platelet activation through the AMPA receptor. J. Exp. Med. 205, 575-584 (2008). [Abstract] [Full Text]