Mochly-Rosen D, Chang F H, Cheever L, Kim M, Diamond I, Gordon A S
Department of Neurology, University of California School of Medicine, San Francisco General Hospital 94110.
Nature. 1988 Jun 30;333(6176):848-50. doi: 10.1038/333848a0.
One of the biochemical results of ethanol exposure is a change in the amount of the intracellular second messenger cyclic AMP (cAMP) produced in response to receptor stimulation. In general, acute ethanol exposure increases the amount of cAMP produced on stimulation of receptors coupled to the enzyme adenylyl cyclase via the GTP-binding protein Gs, whereas chronic ethanol exposure has the opposite effect (results for receptors coupled via Gi have been more variable). We previously reported that adaptation to continuous ethanol exposure reduces receptor-stimulated cAMP production by 25-35% in a neuroblastoma cell line (NG108-15), and an even greater reduction of 75% was observed in lymphocytes taken from actively-drinking alcoholics. This reduction in receptor-stimulated cAMP levels was recently confirmed in platelets from alcoholics. None of these studies, however, determined whether more than one receptor coupled to adenylyl cyclase activity was affected in the same cell. Here we report that chronic ethanol exposure causes desensitization of heterologous receptors coupled to Gs as cAMP production mediated by prostaglandin E1 as well as by adenosine is reduced by approximately 30% in NG108-15 cells. We show that, after chronic ethanol exposure, the activity of the alpha subunit of Gs is decreased by 29%, the amount of alpha s protein is decreased by 38.5%, and alpha s messenger RNA is decreased by 30%. Thus, cellular adaptation to ethanol involves a reduction in alpha s mRNA and, as a consequence, reduced cAMP production by heterologous receptors coupled to Gs. Such changes in cAMP production may account for the tolerance and physical dependence on ethanol in alcoholism.
乙醇暴露的生化结果之一是细胞内第二信使环磷酸腺苷（cAMP）的产生量因受体刺激而发生变化。一般来说，急性乙醇暴露会增加通过鸟苷三磷酸结合蛋白Gs与腺苷酸环化酶偶联的受体受刺激时产生的cAMP量，而慢性乙醇暴露则有相反的作用（通过Gi偶联的受体的结果变化更大）。我们之前报道过，在神经母细胞瘤细胞系（NG108 - 15）中，适应持续乙醇暴露会使受体刺激的cAMP产生量减少25% - 35%，在主动饮酒的酗酒者的淋巴细胞中观察到的减少幅度甚至更大，达到75%。最近在酗酒者的血小板中也证实了受体刺激的cAMP水平的这种降低。然而，这些研究均未确定在同一细胞中是否有不止一种与腺苷酸环化酶活性偶联的受体受到影响。在此我们报道，慢性乙醇暴露会导致与Gs偶联的异源受体脱敏，因为在NG108 - 15细胞中，前列腺素E1以及腺苷介导的cAMP产生减少了约30%。我们表明，慢性乙醇暴露后，Gs的α亚基活性降低了29%，αs蛋白量减少了38.5%，αs信使核糖核酸减少了30%。因此，细胞对乙醇的适应涉及αs信使核糖核酸的减少，结果是与Gs偶联的异源受体产生的cAMP减少。cAMP产生的这种变化可能解释了酗酒中对乙醇的耐受性和身体依赖性。
