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J Biol Chem, Vol. 274, Issue 38, 26985-26991, September 17, 1999

Ethanol-induced Translocation of cAMP-dependent Protein Kinase to the Nucleus
MECHANISM AND FUNCTIONAL CONSEQUENCES

Anastasia Constantinescu, Ivan Diamond^§¶, and Adrienne S. Gordon^§¶

From the Departments of  Neurology, ^§ Cellular and Molecular Pharmacology, and the ^¶ Neuroscience Graduate Program and Center for the Neurobiology of Addiction, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California 94110-3518

Ethanol induces translocation of the catalytic subunit (C) of cAMP-dependent protein kinase (PKA) from the Golgi area to the nucleus in NG108-15 cells. Ethanol also induces translocation of the RII regulatory subunit of PKA to the nucleus; RI and C are not translocated. Nuclear PKA activity in ethanol-treated cells is no longer regulated by cAMP. Gel filtration and immunoprecipitation analysis confirm that ethanol blocks the reassociation of C with RII but does not induce dissociation of these subunits. Ethanol also reduces inhibition of C by the PKA inhibitor PKI. Pre-incubation of C with ethanol decreases phosphorylation of Leu-Arg-Arg-Ala-Ser-Leu-Gly (Kemptide) and casein but has no effect on the phosphorylation of highly charged molecules such as histone H1 or protamine. cAMP-response element-binding protein (CREB) phosphorylation by C is also increased in ethanol-treated cells. This increase in CREB phosphorylation is inhibited by the PKA antagonist (R_p)-cAMPS and by an adenosine receptor antagonist. These results suggest that ethanol affects a cascade of events allowing for sustained nuclear localization of C and prolonged CREB phosphorylation. These events may account for ethanol-induced changes in cAMP-dependent gene expression.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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