Protein Kinase C 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 in neural cell lines.

Here we investigated whether PKC also regulates behavioral responses to ethanol. PKC^–/– mice showed reduced intoxication when administered ethanol and reduced ataxia when administered the nonselective GABA_A receptor agonists pentobarbital and pregnanolone.

However, their response to flunitrazepam was not altered, suggesting that PKC regulates benzodiazepine-insensitive GABA_A receptors, most of which contain subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKC overlapped with GABA_A subunits in thalamus and hippocampus, and ethanol failed to enhance tonic GABA currents in PKC^–/– thalamic and hippocampal neurons.

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

These findings indicate that PKC 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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