Differential expression of guanosine triphosphate binding proteins in men at high and low risk for the future development of alcoholism

We evaluated G-proteins that are components of adenylyl cyclase (AC) signal transduction in erythrocyte and lymphocyte membranes from 26 family history positive (FHP) non-alcoholic and 26 family history negative (FHN) nonalcoholic subjects. Subjects were classified as FHP if their father met criteria for alcohol dependence; as FHN, if there was no history of alcoholism in any first or second degree relatives. Immunoblot analysis indicated that levels of erythrocyte membrane Gsα from FHP subjects were greater than levels in FHN subjects (171±11 vs 100±6, P < 0.001). To confirm the results of the immunoblot analysis, Gsα was quantitated by cholera toxin-dependent [³²P]ADP-ribosylation. Levels of erythrocyte [³²P]ADP-ribose-Gsα from FHP subjects were greater than levels in FHN subjects (236±28 vs 100±14, P < 0.001). Gsα levels did not correlate with age or alcohol consumption. By contrast to differences in Gsα, immunoblot analysis showed similar levels of Gi(2)α and Gi(3)α in erythrocyte membranes of FHP and FHN subjects. Pertussis toxin-catalyzed [³²P]ADP- ribosylation of Gi-like G-proteins confirmed the immunoblot observations. Lastly, compared to FHN subjects, FHP subjects had enhanced Gsα expression in lymphocyte membranes as well (138±11 vs 100±5.5; P < 0.02). In summary, compared to FHN nonalcoholic men, FHP nonalcoholic men had greater levels of the stimulatory G-protein, Gsα, in erythrocyte and lymphocyte membranes. Enhanced expression of Gsα may be a marker of increased risk for the future development of alcoholism.