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Kumar S, Ren Q, Beckley JH, et al. Ethanol Activation of Protein Kinase A Regulates GABA(A) Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis. Front Neurosci. 2012;6:44doi: 10.3389/fnins.2012.00044.
Kumar, S., Ren, Q., Beckley, J. H., O'Buckley, T. K., Gigante, E. D., Santerre, J. L., Werner, D. F., & Morrow, A. L. (2012). Ethanol Activation of Protein Kinase A Regulates GABA(A) Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis. Frontiers in neuroscience, 644. https://doi.org/10.3389/fnins.2012.00044
Kumar, Sandeep, et al. "Ethanol Activation of Protein Kinase A Regulates GABA(A) Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis." Frontiers in neuroscience vol. 6 (2012): 44. doi: https://doi.org/10.3389/fnins.2012.00044
Kumar S, Ren Q, Beckley JH, O'Buckley TK, Gigante ED, Santerre JL, Werner DF, Morrow AL. Ethanol Activation of Protein Kinase A Regulates GABA(A) Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis. Front Neurosci. 2012 Apr 09;6:44. doi: 10.3389/fnins.2012.00044. eCollection 2012. PMID: 22509146; PMCID: PMC3321501.
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Front Neurosci. 2012 Apr 09;6:44. doi: 10.3389/fnins.2012.00044. eCollection 2012.

Ethanol Activation of Protein Kinase A Regulates GABA(A) Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis.

Frontiers in neuroscience

Sandeep Kumar, Qinglu Ren, Jonathon H Beckley, Todd K O'Buckley, Eduardo D Gigante, Jessica L Santerre, David F Werner, A Leslie Morrow

Affiliations

  1. Bowles Center for Alcohol Studies, University of North Carolina School of Medicine Chapel Hill, NC, USA.

PMID: 22509146 PMCID: PMC3321501 DOI: 10.3389/fnins.2012.00044

Abstract

Protein kinases are implicated in neuronal cell functions such as modulation of ion channel function, trafficking, and synaptic excitability. Both protein kinase C (PKC) and A (PKA) are involved in regulation of γ-aminobutyric acid type A (GABA(A)) receptors through phosphorylation. However, the role of PKA in regulating GABA(A) receptors (GABA(A)-R) following acute ethanol exposure is not known. The present study investigated the role of PKA in the effects of ethanol on GABA(A)-R α1 subunit expression in rat cerebral cortical P2 synaptosomal fractions. Additionally, GABA-related behaviors were examined. Rats were administered ethanol (2.0-3.5 g/kg) or saline and PKC, PKA, and GABA(A)-R α1 subunit levels were measured by western blot analysis. Ethanol (3.5 g/kg) transiently increased GABA(A)-R α1 subunit expression and PKA RIIβ subunit expression at similar time points whereas PKA RIIα was increased at later time points. In contrast, PKC isoform expression remained unchanged. Notably, lower ethanol doses (2.0 g/kg) had no effect on GABA(A)-R α1 subunit levels, although PKA type II regulatory subunits RIIα and RIIβ were increased at 10 and 60 min when PKC isozymes are also known to be elevated. To determine if PKA activation was responsible for the ethanol-induced elevation of GABA(A)-R α1 subunits, the PKA antagonist H89 was administered to rats prior to ethanol exposure. H89 administration prevented ethanol-induced increases in GABA(A)-R α1 subunit expression. Moreover, increasing PKA activity intracerebroventricularly with Sp-cAMP prior to a hypnotic dose of ethanol increased ethanol-induced loss of righting reflex (LORR) duration. This effect appears to be mediated in part by GABA(A)-R as increasing PKA activity also increased the duration of muscimol-induced LORR. Overall, these data suggest that PKA mediates ethanol-induced GABA(A)-R expression and contributes to behavioral effects of ethanol involving GABA(A)-R.

Keywords: GABAA receptors; PKA; PKC; ethanol; loss of righting reflex

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