Protein kinase Cdelta regulates ethanol intoxication and enhancement of GABA-stimulated tonic current.
Protein kinase Cdelta regulates ethanol intoxication and enhancement of GABA-stimulated tonic current.
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DOI：
10.1523/jneurosci.3156-08.2008
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发表时间：
2008-11-12
期刊：
影响因子：
--
通讯作者：
Messing RO
中科院分区：
文献类型：
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作者：
Choi DS;Wei W;Deitchman JK;Kharazia VN;Lesscher HM;McMahon T;Wang D;Qi ZH;Sieghart W;Zhang C;Shokat KM;Mody I;Messing RO
乙醇改变神经细胞系中PKCδ的分布和丰度在这里，我们研究了PKCδ是否也调节乙醇的行为反应。PKCδ-/-小鼠在给予乙醇时表现出中毒减轻，在给予非选择性GABAA受体激动剂戊巴比妥和孕烯醇酮时表现出共济失调减轻。然而，它们对氟硝西泮的反应没有改变，表明PKCδ调节苯二氮卓不敏感的GABAA受体，其中大多数含有δ亚基并介导神经元中的紧张性抑制电流。事实上，PKCδ与GABAA δ亚基在丘脑和海马的分布重叠，乙醇不能增强PKCδ-/-丘脑和海马神经元的紧张性GABA电流。此外，在表达α4β3δ GABAA受体的小鼠L（tk-）成纤维细胞中使用ATP类似物敏感的PKCδ突变体，我们发现乙醇增强GABA电流是PKCδ依赖性的。因此，PKCδ增强乙醇中毒部分是通过调节含有δ亚基并介导紧张性抑制电流的GABAA受体。这些发现表明，PKCδ有助于对乙醇的高水平行为反应，这与人类发生酒精使用障碍的风险呈负相关。
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 non-selective 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 GABAA 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.