title: Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits.
abstract: Ethanol enhances gamma-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 epsilon isoform of protein kinase C (PKCepsilon) regulates the ethanol sensitivity of GABA(A) receptors, as mice lacking PKCepsilon show an increased behavioral response to ethanol. Here we developed an ATP analog-sensitive PKCepsilon mutant to selectively inhibit the catalytic activity of PKCepsilon. We used this mutant and PKCepsilon(-/-) mice to determine that PKCepsilon phosphorylates gamma2 subunits at serine 327 and that reduced phosphorylation of this site enhances the actions of ethanol and benzodiazepines at alpha1beta2gamma2 receptors, which is the most abundant GABA(A) receptor subtype in the brain. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol.
authors: Ernest Gallo Clinic and Research Center, Department of Neurology, University of California-San Francisco, 5858 Horton Street, Emeryville, CA 94608, USA.
authors: Zhan-Heng
authors: ZH
authors: Qi
authors: Maengseok
authors: M
authors: Song
authors: Melisa J
authors: MJ
authors: Wallace
authors: Dan
authors: D
authors: Wang
authors: Philip M
authors: PM
authors: Newton
authors: Thomas
authors: T
authors: McMahon
authors: Wen-Hai
authors: WH
authors: Chou
authors: Chao
authors: C
authors: Zhang
authors: Kevan M
authors: KM
authors: Shokat
authors: Robert O
authors: RO
authors: Messing
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity; D012694:Serine / Q000235:genetics / Q000378:metabolism; D000077334:Zolpidem
chemical_list: D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; D012694:Serine; D000077334:Zolpidem; D000255:Adenosine Triphosphate; D051744:Protein Kinase C-epsilon