Chronic ethanol causes heterologous desensitization of receptors by reducing α_smessenger RNA

Abstract

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^1–11. 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 G_s^1,4–8,104"8'10, whereas chronic ethanol exposure has the opposite effect^1,2,7,9,10 (results for receptors coupled via G_i have been more variable). We previously reported that adaptation to continuous ethanol exposure reduces receptor-stimulated cAMP production by 25–35% in a neuroblas-toma cell line (NG108-15)¹, and an even greater reduction of 75% was observed in lymphocytes taken from actively-drinking alcoholics². This reduction in receptor-stimulated cAMP levels was recently confirmed in platelets from alcoholics¹². Nope 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 G_s as cAMP production mediated by prostaglandin E1 as well as by adenosine is reduced by ∼30% in NG108-15 cells. We show that, after chronic ethanol exposure, the activity of the α subunit of G_s is decreased by 29%, the amount of α_s protein is decreased by 38.5%, and α_s messenger RNA is decreased by 30%. Thus, cellular adaptation to ethanol involves a reduction in α_s mRNA and, as a consequence, reduced cAMP production by heterologous receptors coupled to G_s. Such changes in cAMP production may account for the tolerance and physical dependence on ethanol in alcoholism.