Characteristics of endogenous γ-aminobutyric acid (GABA) in human platelets: Functional studies of a novel collagen glycoprotein VI inhibitor

Kuan Hung Lin, Wan-Jung Lu, Shwu Huey Wang, Tsorng Harn Fong, Duen Suey Chou, Chao Chien Chang, Nen Chung Chang, Yung Chen Chiang, Shih Yi Huang, Joen Rong Sheu

研究成果: 雜誌貢獻回顧型文獻同行評審

14 引文 斯高帕斯(Scopus)

摘要

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system, and it also appears in peripheral tissues. Platelets are anuclear blood cells that play a central role in hemostatic processes. Although platelets possess a GABA uptake system, the functional activity of GABA in platelets has remained unclear. We determined that GABA is abundantly distributed in the platelets at a concentration of approximately 1.03 ng/10 6 cells. GABA (0.5 μM) specifically inhibited collagen-induced platelet activation accompanied by [Ca2+]i mobilization, phospholipase Cγ2, protein kinase C, Akt phosphorylation, and hydroxyl radical formation. In addition, GABA interfered with fluorescein isothiocyanate-collagen binding to platelet membranes and produced a concentration-dependent shift in the collagen concentration-response curve and a Schild plot slope of -0.96±0.11, indicating competitive inhibition. Platelet activation induced by convulxin, a glycoprotein VI agonist, was inhibited by GABA, whereas activation induced by the integrin α2β1 agonist, aggretin, was not. Immunoprecipitation and surface plasmon resonance revealed that GABA binds directly to glycoprotein VI in human platelets with equilibrium dissociation (binding) constant (K D) of 41.4 nM. The closure time of whole blood and the occlusion time of platelet plug formation were significantly prolonged by GABA in vivo. In this study, GABA is a specific inhibitor of collagen glycoprotein VI and may be involved in an endogenous negative feedback mechanism for platelet activation. Thus, GABA may represent a potential target for the development of novel interventions for the treatment of cardiovascular diseases associated with platelet activation, such as stroke and myocardial infarction. Key messages: GABA is abundantly distributed in the platelets. GABA inhibited platelet activation stimulated by convulxin. GABA directly associated with glycoprotein VI in platelet membrane. GABA prolonged the closure time of whole blood and the occlusion time of platelet plug formation in vivo.
原文英語
頁(從 - 到)603-614
頁數12
期刊Journal of Molecular Medicine
92
發行號6
DOIs
出版狀態已發佈 - 六月 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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