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(The FASEB Journal. 2000;14:2303-2314.)
© 2000 FASEB

Uncoupling of ßIIPKC from its targeting protein RACK1 in response to ethanol in cultured cells and mouse brain

DORIT RON*,{dagger}1, ALICIA J. VAGTS*, DOUGLAS P. DOHRMAN*,2, RAMI YAKA*, ZHAN JIANG*, LINA YAO*, JOHN CRABBE{ddagger}, JUDITH E. GRISEL{ddagger},3 and IVAN DIAMOND*,{dagger},§

* Ernest Gallo Research Center,
{dagger} Departments of Neurology,
§ Cellular and Molecular Pharmacology, Pediatrics, and Neuroscience Graduate Program and Center for Neurobiology of Addiction, University of California San Francisco, San Francisco, California 94110-3518, USA; and
{ddagger} Portland Alcohol Research Center, Department of Behavioral Neuroscience, Oregon Health Science University and Veterans Affairs Medical Center, Portland, Oregon 97201, USA

1Correspondence: Ernest Gallo Research Center, 5858 Horton St., Suite 200, Emeryville, CA 94608, USA. E-mail: dorit{at}itsa.ucsf.edu

Protein kinase C (PKC) is involved in many neuroadaptive responses to ethanol in the nervous system. PKC activation results in translocation of the enzyme from one intracellular site to another. Compartmentalization of PKC isozymes is regulated by targeting proteins such as receptors for activated C kinase (RACKs). It is possible, therefore, that ethanol-induced changes in the function and compartmentalization of PKC isozymes could be due to changes in PKC targeting proteins. Here we study the response of the targeting protein RACK1 and its corresponding kinase ßIIPKC to ethanol, and propose a novel mechanism to explain how ethanol modulates signaling cascades. In cultured cells, ethanol induces movement of RACK1 to the nucleus without affecting the compartmentalization of ßIIPKC. Ethanol also inhibits ßIIPKC translocation in response to activation. These results suggest that ethanol inhibition of ßIIPKC translocation is due to miscompartmentalization of the targeting protein RACK1. Similar events occurred in mouse brain. In vivo exposure to ethanol caused RACK1 to localize to nuclei in specific brain regions, but did not affect the compartmentalization of ßIIPKC. Thus, some of the cellular and neuroadaptive responses to ethanol may be related to ethanol-induced movement of RACK1 to the nucleus, thereby preventing the translocation and corresponding function of ßIIPKC.—Ron, D., Vagts, A. J., Dohrman, D. P., Yaka, R., Jiang, Z., Yao, L., Crabbe, J., Grisel, J. E., Diamond, I. Uncoupling of ßIIPKC from its targeting protein RACK1 in response to ethanol in cultured cells and mouse brain.


Key Words: PKC • activated C kinase receptor • cAMP • signal transduction • ethanol • targeting protein




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