Alcohol and membrane-associated signal transduction.
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(+)-dependent 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 attained in 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.
Department of Pathology and Cell Biology, Jefferson Medical College, Philadelphia, PA 19107.
J B
JB
Hoek
E
E
Rubin
D000437:Alcoholism / Q000201:enzymology*; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D008563:Membrane Lipids / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects*; D010739:Phospholipase D / Q000502:physiology*; D010740:Phospholipases / Q000502:physiology*; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D010738:Type C Phospholipases / Q000502:physiology*
D008563:Membrane Lipids; D010743:Phospholipids; D000431:Ethanol; D010740:Phospholipases; D010738:Type C Phospholipases; D010739:Phospholipase D