Quantitative Changes in G Proteins Do Not Mediate Ethanol‐Induced Downregulation of Adenylyl Cyclase in Mouse Cerebral Cortex

Abstract

Our prior work, and the work of others, demonstrated that chronic administration of ethanol to cells in culture or to mice resulted in decreased responsiveness of adenylyl cyclase (EC4.6.1.1) to a number of stimulatory agents. In this study, we substantiated the ethanol-induced changes in cerebral cortical adenylyl cyclase activity in alcohol-tolerant and alcohol-dependent mice, and we examined whether chronic ethanol treatment of mice altered the quantity of heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins) in cerebral cortex and other mouse brain areas. Amounts of various G protein subunits--including the alpha subunits of GS (GS alpha), Gi alpha 1-3, G(o) alpha, and beta subunits--were examined by Western blot analysis. There was no change in quantity of these G protein subunits in cerebral cortex, hippocampus, or cerebellum of ethanol-fed mice, compared with controls. In striatum of ethanol-fed mice, small increases in Gi alpha 1 and G(o) alpha were observed, but these changes could not explain the ethanol-induced desensitization of adenylyl cyclase in brain areas such as the cerebral cortex. Forskolin activation of cerebral cortical adenylyl cyclase activity showed two components of activation, with high and low "affinity" for forskolin. Ethanol treatment caused a decrease in the efficacy of forskolin for both components, whereas the EC50 of forskolin for each component did not change. Adenylyl cyclase activity measured in the presence of manganese was also diminished in cortical membranes of ethanol-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroscience of alcoholism: molecular and cellular mechanisms

“…Studies in cell culture and rat cortex demonstrated that acute ethanol exposure could stimulate AC activity and increase cAMP production [68], while chronic ethanol exposure resulted in AC desensitization in mouse cortex [69,70]. AC sensitivity to ethanol was shown to be isoform-specific in transfected human embryonic kidney (HEK293) cells [71].…”

N-Docosahexaenoylethanolamine ameliorates ethanol-induced impairment of neural stem cell neurogenic differentiation

“…While acute ethanol exposure enhanced the agonist-stimulated AC catalytic activity, chronic exposure to ethanol produced adaptive changes in AC function both in animals and in cell cultures (Gobejishvili et al, 2006; Hoffman and Tabakoff, 1990; Rabin, 1990). Desensitization of the AC system by long-term exposure to ethanol is heterologous, as the diminished AC activity was observed in response to a variety of activators (Gordon et al, 1986; Richelson et al, 1986; Tabakoff et al, 1995). Despite parallel observations of inhibited neurogenesis and AC system downregulation caused by chronic ethanol exposure, a direct link between ethanol-induced cAMP regulation and neurogenic differentiation has not been clearly established.…”

Differential effects of ethanol ingestion on somatostatin content, somatostatin receptors and adenylyl cyclase activity in the frontoparietal cortex of virgin and parturient rats

“…Thus, long-term incubation of the NG 108-15 neuroblastoma glioma hybrid cell line with ethanol was not associated with any change in Gia-proteins (Charness et al, 1988). In addition, in vivo studies on chronic ethanol consumption demonstrated no changes in Gi proteins in the cerebral cortex (Tabakoff et al, 1995).…”