Glutamate induces synthesis of thrombogenic peptides and extracellular vesicle release from human platelets

Platelets are highly sensitive blood cells, which play central role in hemostasis and thrombosis. Platelet dense granules carry considerable amount of neurotransmitter glutamate that is exocytosed upon cell activation. As platelets also express glutamate receptors on their surface, it is pertinent to ask whether exposure to glutamate would affect their signalling within a growing thrombus. In this study we demonstrate that, glutamate per se induced synthesis of thrombogenic peptides, plasminogen activator inhibitor-1 and hypoxia-inducible factor-2α, from pre-existing mRNAs in enucleate platelets, stimulated cytosolic calcium entry, upregulated RhoA-ROCK-myosin light chain/myosin light chain phosphatase axis, and elicited extensive shedding of extracellular vesicles from platelets. Glutamate, too, incited platelet spreading and adhesion on to immobilized matrix under arterial shear, raised mitochondrial transmembrane potential associated with generation of reactive oxygen species and induced activation of AMP-activated protein kinase in platelets. Taken together, glutamate switches human platelets to pro-activation phenotype mediated mostly through AMPA receptors and thus targeting glutamate receptors may be a promising anti-platelet strategy.