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Friday, November 14, 2008

Protein Kinase C{delta} Regulates Ethanol Intoxication and Enhancement of GABA-Stimulated Tonic Current
The Journal of Neuroscience, November 12, 2008, 28(46):11890-11899



Ethanol alters the distribution and abundance of PKC{delta} in neural cell lines.

Here we investigated whether PKC{delta} also regulates behavioral responses to ethanol. PKC{delta}–/– 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 PKC{delta} regulates benzodiazepine-insensitive GABAA receptors, most of which contain {delta} subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKC{delta} overlapped with GABAA {delta} subunits in thalamus and hippocampus, and ethanol failed to enhance tonic GABA currents in PKC{delta}–/– thalamic and hippocampal neurons.

Moreover, using an ATP analog-sensitive PKC{delta} mutant in mouse L(tk) fibroblasts that express {alpha}4β3{delta} GABAA receptors, we found that ethanol enhancement of GABA currents was PKC{delta}-dependent. Thus, PKC{delta} enhances ethanol intoxication partly through regulation of GABAA receptors that contain {delta} subunits and mediate tonic inhibitory currents.

These findings indicate that PKC{delta} contributes to a high level of behavioral response to ethanol, which is negatively associated with risk of developing an alcohol use disorder in humans.

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Request Reprint E-Mail: romes@gallo.ucsf.edu
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