Selective chemical genetic inhibition of protein kinase C epsilon reduces ethanol consumption in mice

NEUROPHARMACOLOGY

卷:107

Article

Maiya, Rajani¹  McMahon, Thomas^2,3  Wang, Dan^2,4  Kanter, Benjamin^2,5,6  Gandhi, Dev¹  Chapman, Holly L.^1,7  Miller, Jacklyn²  Messing, Robert O.^1,2 

[1] Univ Texas Austin, Coll Pharm, Div Pharmacol & Toxicol, Austin, TX 78712 USA

[2] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, 5858 Horton St,Suite 200, Emeryville, CA 94608 USA

[3] UCSF Neurol, Box 2911,1550 4th St,Bldg 19B Room 546, San Francisco, CA 94158 USA

[4] UCSF Neurol, Box 1207,675 Nelson Rising Lane,Room 292, San Francisco, CA 94158 USA

[5] Norwegian Univ Sci & Technol, Kavli Inst Syst Neurosci, MTFS, Olav Kyrres Gate 9, N-7489 Trondheim, Norway

[6] Norwegian Univ Sci & Technol, Ctr Neural Computat, MTFS, Olav Kyrres Gate 9, N-7489 Trondheim, Norway

[7] ARS, USDA, Foodborne Toxin Detect & Prevent, 800 Buchanan St, Albany, CA 94710 USA

关键词: Protein kinase C;    Alcohol;    Ethanol;    1-NA-PP1;    AS-Kinase;   

DOI  :  10.1016/j.neuropharm.2016.02.036

来源: Elsevier

【 摘 要 】

Reducing expression or inhibiting translocation of protein kinase C epsilon (PKC epsilon) prolongs ethanol intoxication and decreases ethanol consumption in mice. However, we do not know if this phenotype is due to reduced PKC epsilon kinase activity or to impairment of kinase-independent functions. In this study, we used a chemical-genetic strategy to determine whether a potent and highly selective inhibitor of PKC epsilon catalytic activity reduces ethanol consumption. We generated ATP analog-specific PKC epsilon (AS-PKC epsilon) knock in mice harboring a point mutation in the ATP binding site of PKC epsilon that renders the mutant kinase highly sensitive to inhibition by 1-tert-butyl-3-naphthalen-1-ylpyrazolo[3,4-d]pyrimidin-4-amine (1-NA-PP1). Systemically administered 1-NA-PP1 readily crossed the blood brain barrier and inhibited PKC epsilon-mediated phosphorylation. 1-NA-PP1 reversibly reduced ethanol consumption by AS-PKC epsilon mice but not by wild type mice lacking the AS-PKC epsilon mutation. These results support the development of inhibitors of PKC epsilon Catalytic activity as a strategy to reduce ethanol consumption, and they demonstrate that the AS- PKC epsilon mouse is a useful tool to study the role of PKC epsilon in behavior. (C) 2016 Elsevier Ltd. All rights reserved.

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