Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol
Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol
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DOI：
10.1073/pnas.0801068105
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发表时间：
2008-11-11
影响因子：
11.1
通讯作者：
Treistman, Steven N.
中科院分区：
文献类型：
--
作者：
Martin, Gilles E.;Hendrickson, Linzy M.;Treistman, Steven N.
耐受性，被描述为随着时间的推移药物有效性的丧失，是成瘾的一个重要组成部分。幼稚受试者对酒精表现出的急性行为耐受程度可以预测酒精滥用的可能性。因此，了解急性耐受的决定因素是很重要的。钙和电压门控（BK）钾通道，由孔隙形成α和调节β亚基组成，是乙醇（EtOH）作用的目标。在这里，我们在分子、细胞和行为水平上研究了BK β 4亚基在急性耐受中的作用。HEK-293细胞的单通道记录显示，在缺乏β 4的情况下，EtOH活性增强表现出急性耐受性，这种耐受性通过共表达β 4亚基而被阻断。WT小鼠急性分离的中棘神经元中的BK通道（其中β 4亚基表现良好）表现出很少的耐受性。相反，来自β 4敲除（KO）小鼠的神经元BK通道确实表现出急性耐受性。脑切片记录显示，KO小鼠对EtOH对spike模式的影响具有耐受性，而WT小鼠则没有。此外，β 4 KO小鼠对EtOH的运动效应产生快速耐受性，而WT小鼠则没有。最后，在限制进入乙醇自我给药试验中，β 4 KO小鼠比WT小鼠喝得更多。综上所述，这些数据表明β 4亚基在分子、细胞和行为水平上控制乙醇耐受性，并可能决定酒精滥用和酒精中毒的个体差异，同时也代表了酒精中毒的治疗靶点。
Tolerance, described as the loss of drug effectiveness over time, is an important component of addiction. The degree of acute behavioral tolerance to alcohol exhibited by a naive subject can predict the likelihood of alcohol abuse. Thus, the determinants of acute tolerance are important to understand. Calcium- and voltage-gated (BK) potassium channels, consisting of pore forming alpha and modulatory beta subunits, are targets of ethanol (EtOH) action. Here, we examine the role, at the molecular, cellular, and behavioral levels, of the BK beta 4 subunit in acute tolerance. Single channel recordings in HEK-293 cells show that, in the absence of beta 4, EtOH potentiation of activity exhibits acute tolerance, which is blocked by coexpressing the beta 4 subunit. BK channels in acutely isolated medium spiny neurons from WT mice (in which the beta 4 subunit is well-represented) exhibit little tolerance. In contrast, neuronal BK channels from beta 4 knockout (KO) mice do display acute tolerance. Brain slice recordings showed tolerance to EtOH's effects on spike patterning in KO but not in WT mice. in addition, beta 4 KO mice develop rapid tolerance to EtOH's locomotor effects, whereas WT mice do not. Finally, in a restricted access ethanol self-administration assay, beta 4 KO mice drink more than their WT counterparts. Taken together, these data indicate that the beta 4 subunit controls ethanol tolerance at the molecular, cellular, and behavioral levels, and could determine individual differences in alcohol abuse and alcoholism, as well as represent a therapeutic target for alcoholism.