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J. Biol. Chem., Vol. 282, Issue 45, 33052-33063, November 9, 2007

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Protein Kinase C Regulates -Aminobutyrate Type A Receptor Sensitivity to Ethanol and Benzodiazepines through Phosphorylation of 2 Subunits^*

Zhan-Heng Qi¹, Maengseok Song¹, Melisa J. Wallace, Dan Wang, Philip M. Newton, Thomas McMahon, Wen-Hai Chou, Chao Zhang, Kevan M. Shokat, and Robert O. Messing²

From the Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, Emeryville, California 94608 and the Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143

Ethanol enhances -aminobutyrate (GABA) signaling in the brain, but its actions are inconsistent at GABA_A receptors, especially at low concentrations achieved during social drinking. We postulated that the isoform of protein kinase C (PKC) regulates the ethanol sensitivity of GABA_A receptors, as mice lacking PKC show an increased behavioral response to ethanol. Here we developed an ATP analog-sensitive PKC mutant to selectively inhibit the catalytic activity of PKC. We used this mutant and PKC^-/- mice to determine that PKC phosphorylates 2 subunits at serine 327 and that reduced phosphorylation of this site enhances the actions of ethanol and benzodiazepines at 122 receptors, which is the most abundant GABA_A receptor subtype in the brain. Our findings indicate that PKC phosphorylation of 2 regulates the response of GABA_A receptors to specific allosteric modulators, and, in particular, PKC inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol.

Received for publication, August 28, 2007 , and in revised form, September 17, 2007.

^* This work was supported by National Institutes of Health (NIH) Grant AA013588 and funds provided by the State of California for medical research on alcohol and substance abuse through the University of California at San Francisco (to R. O. M.), and by NIH Grant AI/CA44009 (to K. M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Methods and supplemental Fig. S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Ernest Gallo Clinic and Research Center, 5858 Horton St., Suite 200, Emeryville, CA 94608. Tel.: 510-985-3950; Fax: 510-985-3101; E-mail: romes{at}gallo.ucsf.edu.

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