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- Title
Protein Kinase Cδ Regulates Ethanol Intoxication and Enhancement of GABA-Stimulated Tonic Current.
- Authors
Doo-Sup Choi; Weizheng Wei; Deitchman, J. Kevin; Kharazia, Viktor N.; Lesscher, Heidi M. B.; McMahon, Thomas; Dan Wang; Zhan-Heng Qi; Sieghart, Werner; Chao Zhang; Shokat, Kevan M.; Mody, Istvan; Messing, Robert O.
- Abstract
Ethanol alters the distribution and abundance of PKCδ in neural cell lines. Here we investigated whether PKCδ also regulates behavioral responses to ethanol.PKCδ/mice showed reduced intoxication when administered ethanol and reduced ataxia when administered the nonselective GABAA receptor agonists pentobarbital and pregnanolone. However, their response to flunitrazepam was not altered, suggesting that PKCδ regulates benzodiazepine-insensitive GABAA receptors, most of which contain δ subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKCδ overlapped with GABAA δ subunits in thalamus and hippocampus, and ethanol failed to enhance tonicGABAcurrents inPKCδ-/-thalamic and hippocampal neurons. Moreover, using anATPanalog-sensitive PKCδ mutant in mouse L(tk-) fibroblasts that expressα4β3δ GABAA receptors, we found that ethanol enhancement of GABA currents was PKCδ-dependent. Thus, PKCδ enhances ethanol intoxication partly through regulation of GABAA receptors that contain δ subunits and mediate tonic inhibitory currents. These findings indicate that PKCδ contributes to a high level of behavioral response to ethanol, which is negatively associated with risk of developing an alcohol use disorder in humans.
- Subjects
ALCOHOL; PROTEIN kinase C; NEURAL circuitry; FLUNITRAZEPAM; CELL lines
- Publication
Journal of Neuroscience, 2008, Vol 28, Issue 46, p11890
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3156-08.2008