Somatic localization of a specific large-conductance calcium-activated potassium channel subtype controls compartmentalized ethanol sensitivity in the nucleus accumbens
Somatic localization of a specific large-conductance calcium-activated potassium channel subtype controls compartmentalized ethanol sensitivity in the nucleus accumbens
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DOI：
10.1523/jneurosci.0684-04.2004
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发表时间：
2004-07-21
影响因子：
5.3
通讯作者：
Treistman, S
中科院分区：
文献类型：
--
作者：
Martin, G;Puig, S;Treistman, S
酒精是一种成瘾性药物，靶向各种离子通道和受体。为了解决酒精的影响是否是隔室特异性（索马与树突），我们研究了乙醇（EtOH）对大电导钙激活钾通道（BK）的细胞体和树突的新鲜分离的神经元从大鼠延髓核（NAcc），一个区域已知是关键的发展成瘾。确实观察到隔室特异性药物作用。临床相关浓度的乙醇增加体细胞，但不是树突状BK通道开放的概率。电生理单通道记录和药理学分析的BK通道在切除的补丁从每个区域表明了一些差异，提示一个隔室特异性表达的BK通道的β 4亚基，这可能会解释差异酒精敏感性。这些参数包括活化动力学、钙依赖性和毒素阻断。逆转录-PCR显示，BK通道β 1和β 4亚基mRNA都在NAcc中发现，尽管β 1的信号明显较弱。免疫组化显示，β 1亚单位被发现在索马和树突，而β 4似乎仅限于索马。这些发现表明β 4亚基可能赋予EtOH对体细胞BK通道的敏感性，而树突中β 4的缺失导致对药物不敏感。与此一致的是，急性乙醇增强了转染的人胚肾细胞中的α 4 BK电流，而它未能改变α 1 BK通道介导的电流。最后，乙醇浓度（50 mM），增加BK通道开放的可能性大大降低了持续时间的体细胞产生的动作电位在NAcc神经元。
Alcohol is an addictive drug that targets a variety of ion channels and receptors. To address whether the effects of alcohol are compartment specific (soma vs dendrite), we examined the effects of ethanol (EtOH) on large-conductance calcium-activated potassium channels (BK) in cell bodies and dendrites of freshly isolated neurons from the rat nucleus accumbens (NAcc), a region known to be critical for the development of addiction. Compartment-specific drug action was indeed observed. Clinically relevant concentrations of EtOH increased somatic but not dendritic BK channel open probability. Electrophysiological single-channel recordings and pharmacological analysis of the BK channel in excised patches from each region indicated a number of differences, suggestive of a compartment-specific expression of the beta4 subunit of the BK channel, that might explain the differential alcohol sensitivity. These parameters included activation kinetics, calcium dependency, and toxin blockade. Reverse transcription-PCR showed that both BK channel beta1 and beta4 subunit mRNAs are found in the NAcc, although the signal for beta1 is significantly weaker. Immunohistochemistry revealed that beta1 subunits were found in both soma and dendrites, whereas beta4 appeared restricted to the soma. These findings suggest that the beta4 subunit may confer EtOH sensitivity to somatic BK channels, whereas the absence of beta4 in the dendrite results in insensitivity to the drug. Consistent with this idea, acute EtOH potentiated alphabeta4 BK currents in transfected human embryonic kidney cells, whereas it failed to alter alphabeta1 BK channel-mediated currents. Finally, an EtOH concentration (50 mM) that increased BK channel open probability strongly decreased the duration of somatic-generated action potential in NAcc neurons.