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Inhibition of store-operated Ca(2+) channels prevent ethanol-induced intracellular Ca(2+) increase and cell injury in a human hepatoma cell line
Authors:Liu Huimin  Jia Xiaoqing  Luo Zheng  Guan Hui  Jiang Hong  Li Xuehui  Yan Ming
Affiliation:a Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan 250012, PR China
b The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Shandong University, 107 West Wenhua Road, Jinan 250012, PR China
Abstract:
Elevated intracellular Ca2+ content is implicated in ethanol-induced hepatocyte apoptosis and necrosis. Extracellular Ca2+ influx has been suggested to play a role in this process. However, the exact Ca2+-permeable channel involved in the plasma membrane is still unclear. This study investigated the role of store-operated calcium entry (SOCE) in ethanol-induced cytosolic free Ca2+ concentrations ([Ca2+]i) increase and hepatotoxicity. Ethanol (25-800 mM) dose-dependently increased [Ca2+]i content and hepatocyte damage in HepG2 cells. 2-aminoethoxydiphenyl borate (2-APB), the proved efficient antagonist of SOCs, dose-dependently suppressed the ethanol (200 nM)-increased [Ca2+]i content and protected against ethanol-induced viability loss and transaminase leakage. Exposure to 200 mM ethanol for 24 h significantly upregulated the mRNA and protein expression of calcium release-activated calcium channel protein 1 (CRACM1, Orai1) and stromal interaction molecule 1 (STIM1), the two main molecular constituents of SOCs, which was sustained for at least 72 h. In addition, small interfering RNA knockdown of STIM1 attenuated the ethanol-increased [Ca2+]i content and hepatotoxicity. Taken together, these data indicate that the Ca2+ channel of SOCE may be involved in the pathogenesis of ethanol-induced intracellular Ca2+ elevation and consequent hepatocyte damage.
Keywords:SOCE, store-operated calcium entry   SOCs, store-operated Ca2+ channels   [Ca2+]i, cytosolic free Ca2+ concentrations   2-APB, 2-aminoethoxydiphenyl borate   CRACM1, Orai1, calcium release-activated calcium channel protein 1   STIM1, stromal interaction molecule 1   siRNA, small interfering RNA
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