Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
Sci Rep. 2019 Jun 6;9(1):8346. doi: 10.1038/s41598-019-44734-x.
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.
血小板是高度敏感的血细胞，在止血和血栓形成中起着核心作用。血小板致密颗粒携带相当数量的神经递质谷氨酸，在细胞激活时被外排。由于血小板表面也表达谷氨酸受体，因此有必要询问暴露于谷氨酸是否会影响其在生长中的血栓中的信号转导。在这项研究中，我们证明谷氨酸本身会诱导无核血小板中预先存在的 mRNA 合成血栓形成肽、纤溶酶原激活物抑制剂-1 和缺氧诱导因子-2α，刺激细胞质钙内流，上调 RhoA-ROCK-肌球蛋白轻链/肌球蛋白轻链磷酸酶轴，并引发血小板大量释放细胞外囊泡。谷氨酸还会刺激血小板在动脉剪切下黏附在固定基质上，增加与活性氧生成相关的线粒体跨膜电位，并诱导血小板中 AMP 激活蛋白激酶的激活。总之，谷氨酸使人类血小板转变为主要通过 AMPA 受体介导的促激活表型，因此靶向谷氨酸受体可能是一种有前途的抗血小板策略。
