Single Ethanol Withdrawal Regulates Extrasynaptic δ-GABA(A) Receptors Via PKCδ Activation.
Single Ethanol Withdrawal Regulates Extrasynaptic δ-GABA(A) Receptors Via PKCδ Activation.
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单次乙醇戒断通过 PKCδ 激活调节突触外 δ-GABAA 受体。
DOI：
10.3389/fnmol.2018.00141
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发表时间：
2018
影响因子：
4.8
通讯作者：
Shen Y
中科院分区：
文献类型：
--
作者：
Chen J;He Y;Wu Y;Zhou H;Su LD;Li WN;Olsen RW;Liang J;Zhou YD;Shen Y
酒精（乙醇，EtOH）是最广泛滥用的药物之一，对大脑功能和行为有深远的影响。GABAA受体（GABAAR）是脑中EtOH的主要靶点之一。在体内和体外，GABAARs在单次EtOH暴露后戒断后发生暂时的塑性变化，这可能是慢性EtOH成瘾、耐受和戒断症状的基础。突触外δ-GABAAR内吞作用与乙醇诱导的GABAAR可塑性有关，但乙醇暴露和戒断改变特定GABAAR相对丰度和定位的机制尚不清楚。在这项研究中，我们研究了突触外δ-GABAAR的快速调节的机制，通过一个单一的乙醇撤退在培养的大鼠海马神经元。30分钟EtOH（60 mM）暴露增加突触外强直电流（Itonic）振幅，而不影响神经元中的突触GABAAR功能。相反，在停药后30分钟，强直振幅和对急性EtOH的反应性均降低。在冈田酸（OA）或佛波醇12，13-二丁酸酯（PDBu）暴露的神经元中也发生了类似的结果。蛋白激酶C（PKC）抑制可防止Itonic振幅的降低和对急性EtOH的耐受性，以及由单次EtOH戒断诱导的GABAAR-δ亚基丰度的降低。此外，EtOH戒断选择性地增加PKCδ水平，而PKCδ抑制特异性地挽救EtOH诱导的GABAAR-δ亚基水平和δ-GABAAR功能的改变。总之，我们提供了强有力的证据证明PKCδ在单次乙醇戒断诱导的突触外δ-GABAAR的快速调节中的重要作用。
Alcohol (ethanol, EtOH) is one of the most widely abused drugs with profound effects on brain function and behavior. GABAA receptors (GABAARs) are one of the major targets for EtOH in the brain. Temporary plastic changes in GABAARs after withdrawal from a single EtOH exposure occur both in vivo and in vitro, which may be the basis for chronic EtOH addiction, tolerance and withdrawal symptoms. Extrasynaptic δ-GABAAR endocytosis is implicated in EtOH-induced GABAAR plasticity, but the mechanisms by which the relative abundance and localization of specific GABAARs are altered by EtOH exposure and withdrawal remain unclear. In this study, we investigated the mechanisms underlying rapid regulation of extrasynaptic δ-GABAAR by a single EtOH withdrawal in cultured rat hippocampal neurons. Thirty-minutes EtOH (60 mM) exposure increased extrasynaptic tonic current (Itonic) amplitude without affecting synaptic GABAAR function in neurons. In contrast, at 30 min after withdrawal, Itonic amplitude and responsiveness to acute EtOH were both reduced. Similar results occurred in neurons with okadaic acid (OA) or phorbol 12,13-dibutyrate (PDBu) exposure. Protein kinase C (PKC) inhibition prevented the reduction of Itonic amplitude and the tolerance to acute EtOH, as well as the reduction of GABAAR-δ subunit abundance induced by a single EtOH withdrawal. Moreover, EtOH withdrawal selectively increased PKCδ level, whereas PKCδ inhibition specifically rescued the EtOH-induced alterations in GABAAR-δ subunit level and δ-GABAAR function. Together, we provided strong evidence for the important roles of PKCδ in the rapid regulation of extrasynaptic δ-GABAAR induced by a single EtOH withdrawal.
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影响因子：
4.7
作者：
Bohnsack JP;Carlson SL;Morrow AL
通讯作者：
Morrow AL
影响因子：
4.4
作者：
Carlson, Stephen L.;O'Buckley, Todd K.;Thomas, Rhiannon;Thiele, Todd E.;Morrow, A. Leslie
通讯作者：
Morrow, A. Leslie
DOI：
10.1073/pnas.0506653102
发表时间：
2005-10-11
影响因子：
11.1
作者：
Kittler, JT;Chen, GJ;Moss, SJ
通讯作者：
Moss, SJ
影响因子：
4.3
作者：
Kumar S;Ren Q;Beckley JH;O'Buckley TK;Gigante ED;Santerre JL;Werner DF;Morrow AL
通讯作者：
Morrow AL
影响因子：
3.6
作者：
Cagetti, E;Liang, J;Olsen, RW
通讯作者：
Olsen, RW