Protein kinase Cδ regulates ethanol intoxication and enhancement of GABA-stimulated tonic current

Doo Sup Choi, Weizheng Wei, J. Kevin Deitchman, Viktor N. Kharazia, Heidi M.B. Lesscher, Thomas McMahon, Dan Wang, Zhan Heng Qi, Werner Sieghart, Chao Zhang, Kevan M. Shokat, Istvan Mody, Robert O. Messing

Research output: Contribution to journalArticle

63 Scopus citations

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 tonic GABA currents in PKCδ-/- thalamic and hippocampal neurons. Moreover, using an ATP analog-sensitive PKCδ mutant in mouse L(tk-) fibroblasts that express α4β3δ GABAA receptors, we found that ethanol enhancement of GABA currents was PKCδ-dependent. Thus, PKCδ enhances ethanol intoxication partly through regulation of GABA A 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.

Original languageEnglish (US)
Pages (from-to)11890-11899
Number of pages10
JournalJournal of Neuroscience
Volume28
Issue number46
DOIs
StatePublished - Nov 12 2008

Keywords

  • Ethanol
  • Extrasynaptic
  • GABA
  • Intoxication
  • Protein kinase C
  • Tonic current

ASJC Scopus subject areas

  • Neuroscience(all)

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    Choi, D. S., Wei, W., Deitchman, J. K., Kharazia, V. N., Lesscher, H. M. B., McMahon, T., Wang, D., Qi, Z. H., Sieghart, W., Zhang, C., Shokat, K. M., Mody, I., & Messing, R. O. (2008). Protein kinase Cδ regulates ethanol intoxication and enhancement of GABA-stimulated tonic current. Journal of Neuroscience, 28(46), 11890-11899. https://doi.org/10.1523/JNEUROSCI.3156-08.2008