Sandeep Kumar, Qinglu Ren, Jonathon H. Beckley, Todd K. O’Buckley, Eduardo D. Gigante, Jessica L. Santerre, David F. Werner, A. Leslie Morrow
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.
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 18 April 2012.
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#20,655,488
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#121
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