guanosine-triphosphate and Alcoholism

The adenylyl cyclase (AC) signal transduction pathway is a target of acute and chronic ethanol actions. This study examined whether AC activity in lymphocyte membranes of male alcoholic patients correlated with blood concentrations of ethanol.. Patients (n = 13; mean age: 40 +/- 8 years) were studied on the day of admission (day 0) and 2 days later under detoxification. Moreover, 13 age-matched male healthy controls (mean age 40 +/- 9 years) were included. Lymphocyte membranes were prepared by differential centrifugation whereby blood ethanol was washed out. As a measure of AC activity the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate was determined without (basal activity) and with stimulation of the second messenger system by the guanosine triphosphate (GTP) analogue GTP gamma S (20 mumol/L) via the G-protein or by forskolin (100 mumol/L) acting directly on the AC enzyme.. On day 0, when ethanol blood concentrations were 38-100 mmol/L, we found a significant negative correlation between ethanol blood levels and stimulated AC activities. On day 2, the negative correlation with blood ethanol levels of day 0 had disappeared.. The consumption of ethanol affects the AC system in lymphocytes of alcohol-dependent patients by a persistent effect on the cAMP forming enzyme.

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Adult; Alcoholism; Case-Control Studies; Colforsin; Cyclic AMP; Dose-Response Relationship, Drug; Ethanol; Guanosine Triphosphate; Humans; Longitudinal Studies; Lymphocytes; Male; Middle Aged; Phosphorus Radioisotopes; Signal Transduction

This study investigated alterations in the receptor adenylyl cyclase system in the brain and platelets of alcoholics through the study of GTP binding (G) protein, which has a key role in the system, in the membranes of the post-mortem brain and platelets. Quantitative examination of G protein by immunoblotting showed that GsH alpha in the temporal cortex of the post-mortem alcoholic brain was significantly decreased with controls. Moreover, the extent of ethanol enhancement of functional photoaffinity GTP(azidoanilido GTP) labeling to Gs alpha and Gi alpha was decreased in all cortical regions (frontal, temporal, parietal, occipital cortex) from alcoholics. In the platelet membrane, a quantitative reduction in GsH alpha and GsL alpha levels as assessed by immunoblotting was seen in family history positive (FHP) alcoholics. A reduction in ethanol enhancement of AAGTP labeling to Gs alpha and Gi alpha was also observed in the FHP group. These alterations of G protein were not found in the platelets from family history negative (FHN) alcoholics. The dysfunctions of Gs protein occurring in platelet membranes of the FHP group are likely to parallel those that occur in the alcoholic brain. These results suggest that disturbances of G protein-mediated signal transduction may be involved in the pathophysiology of alcoholics and that platelet G protein may be used as a trait marker of alcoholics.

Topics: Adenylyl Cyclases; Affinity Labels; Alcoholism; Azides; Biomarkers; Blood Platelets; Case-Control Studies; Cerebral Cortex; GTP-Binding Proteins; Guanosine Triphosphate; Humans; In Vitro Techniques; Male; Signal Transduction

The high activities of adenylate cyclase, phosphodiesterase and protein kinases in the synaptic terminals of the central nervous system makes these enzymes prime candidates for the in vivo actions of ethanol. Adult female rats were fed a liquid diet containing ethanol as 35% of the available calories for 6 days. This resulted in a decrease (22-45%) in the basal activity of adenylate cyclase, as determined by cyclic 3',5'-adenosine monophosphate (cAMP) production, in homogenates of all brain areas tested. In these homogenates the ability of guanosine triphosphate and noradrenaline to stimulate basal cyclase activity was severely reduced. These results suggest that ethanol administration causes an uncoupling of the beta-receptor/adenylate cyclase cascade and an interruption of the control of the synthesis of cAMP.

Topics: Adenylyl Cyclases; Alcoholism; Animals; Brain; Ethanol; Female; Guanosine Triphosphate; Kinetics; Norepinephrine; Organ Specificity; Rats; Rats, Inbred Strains; Reference Values

The effects of chronic ethanol administration on striatal and cerebellar adenylate cyclase systems were investigated in the rat. The chronic ethanol treatment resulted in behavioral tolerance, but no difference in the sensitivity of adenylate cyclase to in vitro ethanol was observed. In one set of experiments using 173-195 g rats, GTP-, dopamine- and NaF-stimulated adenylate cyclase activities in the striatum were higher in rats chronically treated with ethanol when compared to animals pair-fed the liquid diet. However, no difference in adenylate cyclase activity was observed in cerebellar or striatal tissues when larger rats (280-385 g) were used. In conclusion, an adaptive change in activation of adenylate cyclase by in vitro ethanol does not occur after chronic ethanol treatment. The observed changes in enzyme activity measured in the absence of in vitro ethanol do not appear to be a simple, direct effect of chronic ethanol treatment.

Topics: Adenylyl Cyclases; Alcoholism; Animals; Cerebellum; Corpus Striatum; Dopamine; Drug Resistance; Ethanol; Guanosine Triphosphate; In Vitro Techniques; Male; Rats; Rats, Inbred Strains; Sodium-Potassium-Exchanging ATPase

Topics: Adenylyl Cyclases; Alcoholism; Animals; Cell Membrane; Cholera Toxin; Corpus Striatum; Cyclic AMP; Ethanol; Guanosine Triphosphate; Male; Rats; Rats, Inbred Strains