Kinetic and structural determinants for GABA-A receptor potentiation by neuroactive steroids.
Kinetic and structural determinants for GABA-A receptor potentiation by neuroactive steroids.
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DOI：
10.2174/157015910790909458
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发表时间：
2010-03
影响因子：
5.3
通讯作者：
Steinbach JH
中科院分区：
文献类型：
--
作者：
Akk G;Covey DF;Evers AS;Mennerick S;Zorumski CF;Steinbach JH
内源性神经类固醇和合成的神经活性类固醇类似物是哺乳动物GABA-A受体最有效和最有效的增强剂之一。这些化合物与受体上的一个或多个部位相互作用，通过一系列开放和关闭时间分布的变化，导致通道开放概率的增加。内源性神经类固醇激素别孕酮通过增加最长开放时间成分的平均持续时间和发生率以及通过降低最长寿命的簇内关闭时间成分的发生率来增强α1β2γ2L GABA-A受体。因此，增加了通道的平均打开时间，减少了平均关闭时间，从而增强了通道功能。其他一些先前描述的神经类固醇和类固醇类似物通过类似的机制发挥作用，而其他一些则影响这些参数的子集。类固醇通过与GABA-A受体的跨膜区域相互作用来调节该受体。然而，调节类固醇作用的结合位点的数量尚不清楚。我们讨论了支持单部位与多部位的概念的数据，这些数据介导了类固醇的增强作用。
Endogenous neurosteroids and synthetic neuroactive steroid analogs are among the most potent and efficacious potentiators of the mammalian GABA-A receptor. The compounds interact with one or more sites on the receptor leading to an increase in the channel open probability through a set of changes in the open and closed time distributions. The endogenous neurosteroid allopregnanolone potentiates the α1β2γ2L GABA-A receptor by enhancing the mean duration and prevalence of the longest-lived open time component and by reducing the prevalence of the longest-lived intracluster closed time component. Thus the channel mean open time is increased and the mean closed time duration is decreased, resulting in potentiation of channel function. Some of the other previously characterized neurosteroids and steroid analogs act through similar mechanisms while others affect a subset of these parameters. The steroids modulate the GABA-A receptor through interactions with the membrane-spanning region of the receptor. However, the number of binding sites that mediate the actions of steroids is unclear. We discuss data supporting the notions of a single site vs. multiple sites mediating the potentiating actions of steroids.
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