Glutamate mediates platelet activation through the AMPA receptor

Abstract

Glutamate is an excitatory neurotransmitter that binds to the kainate receptor, the N-methyl-D-aspartate (NMDA) receptor, and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR). Each receptor was first characterized and cloned in the central nervous system (CNS). Glutamate is also present in the periphery, and glutamate receptors have been identified in nonneuronal tissues, including bone, heart, kidney, pancreas, and platelets. Platelets play a central role in normal thrombosis and hemostasis, as well as contributing greatly to diseases such as stroke and myocardial infarction. Despite the presence of glutamate in platelet granules, the role of glutamate during hemostasis is unknown. We now show that activated platelets release glutamate, that platelets express AMPAR subunits, and that glutamate increases agonist-induced platelet activation. Furthermore, we demonstrate that glutamate binding to the AMPAR increases intracellular sodium concentration and depolarizes platelets, which are important steps in platelet activation. In contrast, platelets treated with the AMPAR antagonist CNQX or platelets derived from GluR1 knockout mice are resistant to AMPA effects. Importantly, mice lacking GluR1 have a prolonged time to thrombosis in vivo. Our data identify glutamate as a regulator of platelet activation, and suggest that the AMPA receptor is a novel antithrombotic target

Platelet Kainate Receptor Signaling Promotes Thrombosis by Stimulating Cyclooxygenase Activation

“…Our previous studies demonstrated that glutamate pre-treatment increased agonist induced platelet activation 1. Glutamate by itself does not directly alter the expression of surface markers of platelet activation, such as GPIIb/IIIa activation (PAC-1 antibody binding) and P-selectin expression1.…”

“…Most peripheral glutamate receptors when cloned and sequenced are identical to those of the CNS 7. We have previously demonstrated using a real time glutamate sensitive enzymatic probe that glutamate reaches very high concentrations (greater than 400 μM) within a developing thrombus1. We have also demonstrated that glutamate signaling has an important role in efficient thrombus formation by amplifying platelet activation, in part through platelet expressed AMPA receptors 1.…”

“…These include changes in intracellular ion concentrations and pH, conformational changes in receptors such as Glycoprotein IIb/IIIa (GPIIb/IIIa), granule exocytosis, and secretion of vasoactive mediators. Many granule constituents are shared between platelets and neurons including Substance P, ADP, ATP, serotonin, and glutamate 1-3. Glutamate signaling is well explored in the brain, but glutamate effects on platelet function are less well studied and only beginning to be understood.…”

Peripheral Biomarkers Revisited: Integrative Profiling of Peripheral Samples for Psychiatric Research

“…They express a broad range of neurotransmitter receptors and transporters (17). Therefore, it is not surprising that platelets have been extensively used to examine the functional properties of receptors and transporter activities (see Neurotransmission).…”

Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy

“…The AMPAR subtype iGluRs exhibit kinetics at the millisecond timescale, and mediate fast neurotransmission in excitatory synapses, directly impacting synaptic plasticity, learning, and memory (1). Aberrations in AMPAR function are implicated in a wide range of diseases, from developmental diseases such as Fragile-X syndrome (3), to psychiatric disorders (1), acute trauma in ischemic stroke (4, 5), epileptic seizures (6, 7) and chronic neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases (1). …”