A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition
A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition
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DOI：
10.1016/j.neuropharm.2016.04.031
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发表时间：
2016-09-01
影响因子：
4.7
通讯作者：
Mennerick, Steven
中科院分区：
文献类型：
--
作者：
Jiang, Xiaoping;Shu, Hong-Jin;Mennerick, Steven
麻醉剂、GABA活性神经类固醇可有效增强GABA（A）受体功能，导致重要的行为后果。神经类固醇及其合成类似物也是多种细胞渗透性神经活性化合物的模型。细胞渗透和区室化提高了这些化合物的作用受其细胞分配影响的可能性，但这些贡献通常不被实验或治疗考虑。为了研究神经类固醇的细胞积累和药效学之间的相互作用，我们合成了一种新的化学生物学类似物（生物活性，可点击的光标记）的GABA活性神经类固醇。我们发现，类似物选择性地光标记大鼠海马神经元中的神经元高尔基体。活性类似物的选择性分布是不同的内源性胆固醇和不完全共享的一些非GABA活性，神经类固醇类似物。另一方面，该分布不是对映选择性的，并且不需要能量，与文献中最近的其他先例相反。我们表明，体细胞选择性积累可以作为一个水槽或源类固醇作用在质膜GABA受体，改变稳态和时间过程中的影响，在体细胞GABAA受体相对于树突状受体。我们的研究结果表明，在质膜受体的隔室选择性药物作用的新机制。(C)2016爱思唯尔有限公司版权所有
Anesthetic, GABA-active neurosteroids potently augment GABA(A) receptor function, leading to important behavioral consequences. Neurosteroids and their synthetic analogues are also models for a wide variety of cell-permeant neuroactive compounds. Cell permeation and compartmentalization raise the possibility that these compounds' actions are influenced by their cellular partitioning, but these contributions are not typically considered experimentally or therapeutically. To examine the interplay between cellular accumulation and pharmacodynamics of neurosteroids, we synthesized a novel chemical biology analogue (bio-active, clickable photolabel) of GABA-active neurosteroids. We discovered that the analogue selectively photo-labels neuronal Golgi in rat hippocampal neurons. The active analogue's selective distribution was distinct from endogenous cholesterol and not completely shared by some non-GABA active, neurosteroid-like analogues. On the other hand, the distribution was not enantioselective and did not require energy, in contrast to other recent precedents from the literature. We demonstrate that the soma-selective accumulation can act as a sink or source for steroid actions at plasma-membrane GABA receptors, altering steady-state and time course of effects at somatic GABAA receptors relative to dendritic receptors. Our results suggest a novel mechanism for compartment-selective drug actions at plasma-membrane receptors. (C) 2016 Elsevier Ltd. All rights reserved.