Study on the role of ethanol-induced apoptosis and signal transduction system in the pathophysiology of alcohol/drug dependence.

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Our previous studies suggest that the quantitative and qualitative reduction of certain G proteins and type I adenylyl cyclase (AC-I) are related to the features of human alcoholics, indicating that cAMP-mediated signal transduction is disordered in alcoholic brain. Since cAMP-regulated gene transcription via CREB has been demonstrated to have a crucial role in the brain function, we investigated the amounts of both CREB and its phosphorylated form in the postmortem human brains. Although the amount of neither CREB nor phosphorylated CREB significantly changed in the alcoholic brains regardless of the different regions compared to controls, further investigation is needed to elucidate the molecular mechanism for the alteration of cAMP-mediated signal transduction in alcoholics. On the other hand, it has also been pointed out that sever alcoholics are often accompanied with a brain atrophy via a disorder of cellular Ca^<2+>-system. Annexin IV, a Ca^<2+> /lipid binding protein, was signi … More ficantly augmented in amount in the postmortem brains (the hippocampus) of alcoholics. In addition, the alcoholic patients tended to have autoantibodies to annexin IV. Using cultured cells (rat glioma C6 cells and human adenocarcinoma A549 cells), it was shown that the intrinsic amount of annexin IV was increased by the exposure to ethanol in the both cells, whereas levels of annexins I and V were unchanged. The mitochondrial dehydrogenae activity, which is an index for monitoring cell lesion (apoptosis), was decreased and caspase 3 activity was increased with a high concentration of ethanol (200 mM or more) after 12 or 24h-exposure, but the amount of annexin IV was increased even with a low concentration of ethanol (50 mM) at which cell damage had not been induced. Interestingly, the overexpression of annexin IV in C6 cells by transfection with annexin IV-DNA enhanced ethanol-induced cell lesion and was accompanied by NFkB activation. Thus, it might be indicated that the amount of annexin IV is selectively augmented and this augmentation facilitates the development of cell lesion by ethanol. Less