Ethanol Activation of Protein Kinase A Regulates GABA(A) Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis.
Ethanol Activation of Protein Kinase A Regulates GABA(A) Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis.
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DOI：
10.3389/fnins.2012.00044
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发表时间：
2012
影响因子：
4.3
通讯作者：
Morrow AL
中科院分区：
文献类型：
--
作者：
Kumar S;Ren Q;Beckley JH;O'Buckley TK;Gigante ED;Santerre JL;Werner DF;Morrow AL
蛋白激酶参与神经元细胞功能，如离子通道功能、运输和突触兴奋性的调节。蛋白激酶C（PKC）和蛋白激酶A（PKA）均通过磷酸化参与γ-氨基丁酸A型（GABAA）受体的调节。然而，PKA在急性乙醇暴露后调节GABAA受体（GABAA-R）的作用尚不清楚。本研究探讨PKA在乙醇对大鼠大脑皮层P2突触体GABAA-R α1亚单位表达的影响中的作用。此外，还检查了GABA相关行为。给大鼠注射乙醇（2.0-3.5 g/kg）或生理盐水，通过蛋白质印迹分析测定PKC、PKA和GABAA-R α1亚基水平。乙醇（3.5 g/kg）在相似时间点短暂增加GABAA-R α1亚基表达和PKA RIIβ亚基表达，而PKA RIIα在稍后时间点增加。相反，PKC亚型表达保持不变。值得注意的是，较低乙醇剂量（2.0 g/kg）对GABAA-R α1亚基水平没有影响，尽管在10和60 min时PKC同工酶也升高时PKA II型调节亚基RIIα和RIIβ增加。为了确定PKA激活是否是乙醇诱导的GABAA-R α1亚基升高的原因，在乙醇暴露前给予大鼠PKA拮抗剂H89。H89给药阻止乙醇诱导的GABAA-R α1亚基表达增加。此外，增加PKA活性脑室内与Sp-cAMP之前，催眠剂量的乙醇增加乙醇诱导的翻正反射（LORR）的持续时间的损失。这种效应似乎部分由GABAA-R介导，因为PKA活性增加也增加了蝇蕈醇诱导的LORR的持续时间。总之，这些数据表明，PKA介导乙醇诱导的GABAA-R的表达，并有助于乙醇涉及GABAA-R的行为效应。
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 (GABAA) receptors through phosphorylation. However, the role of PKA in regulating GABAA receptors (GABAA-R) following acute ethanol exposure is not known. The present study investigated the role of PKA in the effects of ethanol on GABAA-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 GABAA-R α1 subunit levels were measured by western blot analysis. Ethanol (3.5 g/kg) transiently increased GABAA-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 GABAA-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 GABAA-R α1 subunits, the PKA antagonist H89 was administered to rats prior to ethanol exposure. H89 administration prevented ethanol-induced increases in GABAA-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 GABAA-R as increasing PKA activity also increased the duration of muscimol-induced LORR. Overall, these data suggest that PKA mediates ethanol-induced GABAA-R expression and contributes to behavioral effects of ethanol involving GABAA-R.
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影响因子：
2.5
作者：
Kapur, J;Macdonald, RL
通讯作者：
Macdonald, RL
影响因子：
4.8
作者：
Brandon, NJ;Delmas, P;Moss, SJ
通讯作者：
Moss, SJ
影响因子：
5.7
作者：
Lai, Chih-Chia;Kuo, Ting-In;Lin, Hsun-Husn
通讯作者：
Lin, Hsun-Husn
影响因子：
3.3
作者：
GLANTZ, SB;AMAT, JA;RUBIN, CS
通讯作者：
RUBIN, CS
DOI：
10.1124/jpet.106.110890
发表时间：
2006-12-01
影响因子：
3.5
作者：
Kumar, S.;Lane, B. M.;Morrow, A. L.
通讯作者：
Morrow, A. L.