title: Chronic ethanol-induced heterologous desensitization is mediated by changes in adenosine transport.
abstract: Chronic exposure of cultured cell lines to ethanol results in a heterologous desensitization of receptors coupled to adenylate cyclase via GS, the stimulatory guanine nucleotide regulatory protein. This heterologous desensitization is accompanied by a decrease in alpha S, the GTP-binding subunit of GS. Ethanol-induced accumulation of extracellular adenosine is required for the development of heterologous desensitization. To determine the mechanism underlying the ethanol-dependent increase in extracellular adenosine, we investigated the effects of ethanol on the nucleoside transporter responsible for the bidirectional transport of adenosine into and out of the cell. We found that ethanol specifically and non-competitively inhibited nucleoside uptake. Inhibition of adenosine uptake was primarily due to decreased influx via the nucleoside transporter. Thus, ethanol-induced increases in extracellular adenosine appear to be due to inhibition of adenosine influx. After chronic exposure to ethanol, cells became tolerant to the acute effects of ethanol, i.e. ethanol no longer inhibited uptake and, consequently, no longer increased extracellular adenosine concentration. Taken together with our previous studies, these results suggest that acute ethanol inhibition of adenosine influx leads to an increase in extracellular adenosine which in turn activates adenosine A2 receptors to increase cyclic AMP levels, leading to desensitization of receptor-dependent cyclic AMP signal transduction after chronic exposure to ethanol. We next determined whether the same effects of ethanol also occur in alcoholics. We isolated lymphocytes from alcoholics and non-alcoholics and found that alcoholics had a 75% decrease in basal and adenosine receptor-stimulated cyclic AMP production compared with non-alcoholics. To determine whether these differences were due to exposure to ethanol in vivo or to a possible genetic difference between alcoholics and non-alcoholics, we grew lymphocytes in culture in the absence of ethanol. Adenosine receptor-stimulated cyclic AMP levels were higher in alcoholics than non-alcoholics. Moreover, cultured cells from alcoholics were more sensitive to the effects of chronic alcohol on cyclic AMP signal transduction than cells from non-alcoholics. Our results suggest that the cyclic AMP signal transduction system may reflect a genetic alteration in alcoholics and that studies in cultured lymphocytes may allow us to identify individuals at risk of developing alcoholism.
authors.affiliation: Ernest Gallo Clinic and Research Center, San Francisco General Hospital, CA 94110.
authors.forename: A S
authors.initials: AS
authors.lastname: Gordon
authors.forename: L
authors.initials: L
authors.lastname: Nagy
authors.forename: D
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: I
authors.initials: I
authors.lastname: Diamond
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000437:Alcoholism / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D011983:Receptors, Purinergic / Q000187:drug effects*; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D011983:Receptors, Purinergic; D000431:Ethanol; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000241:Adenosine