Choi Doo-Sup, Wei Weizheng, Deitchman J Kevin, Kharazia Viktor N, Lesscher Heidi M B, McMahon Thomas, Wang Dan, Qi Zhan-Heng, Sieghart Werner, Zhang Chao, Shokat Kevan M, Mody Istvan, Messing Robert O
Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, USA.
J Neurosci. 2008 Nov 12;28(46):11890-9. doi: 10.1523/JNEUROSCI.3156-08.2008.
Ethanol alters the distribution and abundance of PKCdelta in neural cell lines. Here we investigated whether PKCdelta also regulates behavioral responses to ethanol. PKCdelta(-/-) mice showed reduced intoxication when administered ethanol and reduced ataxia when administered the nonselective GABA(A) receptor agonists pentobarbital and pregnanolone. However, their response to flunitrazepam was not altered, suggesting that PKCdelta regulates benzodiazepine-insensitive GABA(A) receptors, most of which contain delta subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKCdelta overlapped with GABA(A) delta subunits in thalamus and hippocampus, and ethanol failed to enhance tonic GABA currents in PKCdelta(-/-) thalamic and hippocampal neurons. Moreover, using an ATP analog-sensitive PKCdelta mutant in mouse L(tk(-)) fibroblasts that express alpha4beta3delta GABA(A) receptors, we found that ethanol enhancement of GABA currents was PKCdelta-dependent. Thus, PKCdelta enhances ethanol intoxication partly through regulation of GABA(A) receptors that contain delta subunits and mediate tonic inhibitory currents. These findings indicate that PKCdelta contributes to a high level of behavioral response to ethanol, which is negatively associated with risk of developing an alcohol use disorder in humans.
乙醇会改变神经细胞系中蛋白激酶Cδ（PKCδ）的分布和丰度。在此，我们研究了PKCδ是否也调控对乙醇的行为反应。给予乙醇时，PKCδ基因敲除（PKCδ(-/-)）小鼠的醉酒程度减轻，给予非选择性γ-氨基丁酸A（GABA(A)）受体激动剂戊巴比妥和孕烷醇酮时，共济失调减轻。然而，它们对氟硝西泮的反应未改变，这表明PKCδ调控对苯二氮䓬不敏感的GABA(A)受体，其中大多数含有δ亚基并介导神经元的紧张性抑制电流。实际上，PKCδ在丘脑和海马中的分布与GABA(A)δ亚基重叠，乙醇未能增强PKCδ(-/-)丘脑和海马神经元中的紧张性GABA电流。此外，在表达α4β3δ GABA(A)受体的小鼠L(tk(-))成纤维细胞中使用对ATP类似物敏感的PKCδ突变体，我们发现乙醇对GABA电流的增强作用依赖于PKCδ。因此，PKCδ部分通过调控含有δ亚基并介导紧张性抑制电流的GABA(A)受体来增强乙醇中毒。这些发现表明，PKCδ促成了对乙醇的高水平行为反应，而这与人类发生酒精使用障碍的风险呈负相关。
