ALCOHOL AND MEMBRANE-ASSOCIATED SIGNAL TRANSDUCTION
ALCOHOL AND MEMBRANE-ASSOCIATED SIGNAL TRANSDUCTION
复制标题
DOI：
10.1093/oxfordjournals.alcalc.a044989
复制
发表时间：
1990-01-01
影响因子：
2.8
通讯作者：
RUBIN, E
中科院分区：
文献类型：
--
作者：
HOEK, JB;RUBIN, E
近年来，乙醇被证明与膜相关的信号转导机制相互作用，这种机制依赖于磷脂酶与其在膜上的磷脂底物的反应。在几种细胞和膜制剂中，乙醇激活多磷肌醇特异性磷脂酶C，并触发完整的细胞内信号反应，这是激素通过这一途径所特有的，包括形成肌醇-1，4，5-三磷酸，从细胞内储存部位释放钙从而激活胞内钙酶，形成二酰甘油，从而刺激蛋白激酶C。磷脂酶C的激活似乎是由于乙醇与受体-G蛋白-磷脂酶C膜内复合体的相互作用，可能促进了结合的GDP的释放和GTP的结合，以激活控制磷脂酶C活性的G-蛋白。在许多完整的细胞中，磷脂酶C受到蛋白激酶C的反馈抑制控制，在肝细胞中，乙醇也触发这种反馈抑制，导致磷脂酶C活性迅速下降；同时，乙醇还导致对加压素和其他磷脂酶C相关激动剂的反应脱敏。在激素浓度在生理范围内，乙醇对激动剂介导的磷脂酶C激活的异源脱敏作用可能是乙醇浓度在体内容易获得的一个重要因素。乙醇与细胞内第二信使系统的进一步相互作用是通过激素敏感的磷脂酶D介导的。该酶利用磷脂酰胆碱产生磷脂酸，磷脂酸可以进一步转化为二酰甘油。在乙醇存在下，该酶催化磷脂酰化为磷脂酰乙醇。然而，目前还不清楚在什么条件下，这一过程会影响第二信使分子的正常形成模式。慢性摄入乙醇后，在细胞水平上可以对乙醇对激动剂诱导的信号转导过程的影响产生耐受性。然而，这种耐受性的形成机制目前还是一个猜测。对肝细胞的研究表明，蛋白激酶C的活性可能在这种类型的乙醇耐受性的形成中发挥作用。更好地了解乙醇与这些磷脂依赖的信号转导过程的相互作用，可以为乙醇干扰多种细胞和组织的生理调控机制指明机制。
In recent years, ethanol has been shown to interact with membrane-associated signal transduction mechanisms which rely on the reaction of phospholipases with their phospholipid substrates in the membrane. In several cell and membrane preparations, ethanol activates the polyphosphoinositide-specific phospholipase C and triggers the complete battery of intracellular signalling responses that are characteristic for hormones acting through this pathway, including the formation of inositol-1,4,5-trisphosphate, the release of Ca2+from intracellular storage sites with the consequent activation of cytosolic Ca2+enzymes, and the formation of diacylglycerol leading to the stimulation of protein kinase C. The activation of phospholipase C appears to be due to an interaction of ethanol with the intramembrane complex of receptor-G protein-phospholipase C, presumably promoting the release of bound GDP and the binding of GTP to activate the G-protein which controls phospholipase C activity. In many intact cells, the phospholipase C is subject to a feedback inhibitory control by protein kinase C. In liver cells, ethanol also triggers this feedback inhibition, leading to a rapid decline in the phospholipase C activation; at the same time, ethanol also causes the desensitization of the response to vasopressin and other phospholipase C-linked agonists. At hormone concentrations in the physiological range, the heterologous desensitization by ethanol of the agonist-mediated phospholipase C activation may be a significant factor at ethanol concentrations that are readily attainedin vivo. Further interaction of ethanol with the intracellular second messenger system is mediated through a hormone-sensitive phospholipase D. This enzyme uses phosphatidylcholine to generate phosphatidic acid which can be further converted to diacylglycerol. In the presence of ethanol the enzyme catalyzes the transphosphatidylation to phosphatidylethanol. It is not clear, however, under what conditions this process could affect the normal pattern of formation of second messenger molecules. After chronic ethanol intake, a tolerance can develop at the cellular level to the effects of ethanol on agonist-induced signal transduction processes. However, the mechanism by which this tolerance develops is currently a matter of conjecture. Studies on liver cells indicate that the activity of protein kinase C may play a role in the development of this type of tolerance to ethanol. A better understanding of the interaction of ethanol with these phospholipid-dependent signal transduction processes could point to mechanisms by which ethanol could interfere with physiological control mechanism in a variety of cells and tissues.