title: Inhibition of store-operated Ca(2+) channels prevent ethanol-induced intracellular Ca(2+) increase and cell injury in a human hepatoma cell line.
abstract: Elevated intracellular Ca(2+) content is implicated in ethanol-induced hepatocyte apoptosis and necrosis. Extracellular Ca(2+) influx has been suggested to play a role in this process. However, the exact Ca(2+)-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 Ca(2+) concentrations ([Ca(2+)](i)) increase and hepatotoxicity. Ethanol (25-800mM) dose-dependently increased [Ca(2+)](i) content and hepatocyte damage in HepG2 cells. 2-aminoethoxydiphenyl borate (2-APB), the proved efficient antagonist of SOCs, dose-dependently suppressed the ethanol (200nM)-increased [Ca(2+)](i) content and protected against ethanol-induced viability loss and transaminase leakage. Exposure to 200mM ethanol for 24h 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 72h. In addition, small interfering RNA knockdown of STIM1 attenuated the ethanol-increased [Ca(2+)](i) content and hepatotoxicity. Taken together, these data indicate that the Ca(2+) channel of SOCE may be involved in the pathogenesis of ethanol-induced intracellular Ca(2+) elevation and consequent hepatocyte damage.
authors: Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan 250012, PR China.
authors: Huimin
authors: H
authors: Liu
authors: Xiaoqing
authors: X
authors: Jia
authors: Zheng
authors: Z
authors: Luo
authors: Hui
authors: H
authors: Guan
authors: Hong
authors: H
authors: Jiang
authors: Xuehui
authors: X
authors: Li
authors: Ming
authors: M
authors: Yan
mesh_terms: D015153:Blotting, Western; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D000431:Ethanol / Q000037:antagonists & inhibitors / Q000633:toxicity*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000071740:ORAI1 Protein; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071737:Stromal Interaction Molecule 1
chemical_list: D001896:Boron Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D000431:Ethanol; C109986:2-aminoethoxydiphenyl borate; D002118:Calcium