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The Journal of Neuroscience, November 12, 2008, 28(46):11890-11899; doi:10.1523/JNEUROSCI.3156-08.2008

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Cellular/Molecular
Protein Kinase C Regulates Ethanol Intoxication and Enhancement of GABA-Stimulated Tonic Current

Doo-Sup Choi,¹ Weizheng Wei,² J. Kevin Deitchman,¹ Viktor N. Kharazia,¹ Heidi M. B. Lesscher,¹ Thomas McMahon,¹ Dan Wang,¹ Zhan-Heng Qi,¹ Werner Sieghart,³ Chao Zhang,⁴ Kevan M. Shokat,⁴ Istvan Mody,² and Robert O. Messing¹

¹Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, ²Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, ³Division of Biochemistry and Molecular Biology, Centre for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria, and ⁴Department of Cellular and Molecular Pharmacology and the Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143

Correspondence should be addressed to Dr. Robert O. Messing, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: romes{at}gallo.ucsf.edu

Ethanol alters the distribution and abundance of PKC in neural cell lines. Here we investigated whether PKC also regulates behavioral responses to ethanol. PKC^–/– mice showed reduced intoxication when administered ethanol and reduced ataxia when administered the nonselective GABA_A receptor agonists pentobarbital and pregnanolone. However, their response to flunitrazepam was not altered, suggesting that PKC regulates benzodiazepine-insensitive GABA_A receptors, most of which contain subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKC overlapped with GABA_A subunits in thalamus and hippocampus, and ethanol failed to enhance tonic GABA currents in PKC^–/– thalamic and hippocampal neurons. Moreover, using an ATP analog-sensitive PKC mutant in mouse L(tk^–) fibroblasts that express 4β3 GABA_A receptors, we found that ethanol enhancement of GABA currents was PKC-dependent. Thus, PKC enhances ethanol intoxication partly through regulation of GABA_A receptors that contain subunits and mediate tonic inhibitory currents. These findings indicate that PKC contributes to a high level of behavioral response to ethanol, which is negatively associated with risk of developing an alcohol use disorder in humans.

Key words: protein kinase C; ethanol; GABA; tonic current; intoxication; extrasynaptic

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Received July 3, 2008; revised Sept. 3, 2008; accepted Sept. 29, 2008.

Correspondence should be addressed to Dr. Robert O. Messing, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: romes{at}gallo.ucsf.edu

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