Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance
Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance
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DOI：
10.1016/j.neuroscience.2005.07.021
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发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Lambert, JJ
中科院分区：
文献类型：
--
作者：
Belelli, D;Herd, MB;Lambert, JJ
GABA（A）受体介导的抑制功能障碍与许多神经和精神疾病（包括癫痫和情感障碍）有关。这些病症中的一些与某些内源性神经类固醇的异常水平有关，这些类固醇有效地和选择性地增强大脑的主要抑制性受体GABA（A）受体的功能。与其增强神经元抑制的能力一致，此类类固醇在动物和人类中表现出抗焦虑、抗惊厥和麻醉作用。神经类固醇，例如有效的孕酮代谢物5 α-胆甾烷-3 α-醇-20-酮，可以在CNS中神经元和神经胶质中以足以调节GABA（A）受体功能的水平从头合成。神经类固醇水平不是静态的，而是受到动态波动的影响，例如在压力或怀孕后期。这些观察结果表明，这些内源性调节剂可以细化脑的主要抑制性受体的功能，从而发挥重要的生理和病理生理作用。然而，考虑到GABA（A）受体在整个哺乳动物CNS中的普遍表达，神经类固醇水平的变化应该是广泛经历的，引起神经元抑制的普遍增强。这种非特异性作用似乎与生理作用不相容。然而，神经类固醇的作用既是大脑区域的，也是神经元的选择性的。这种特异性由多种分子机制引起，包括受体亚基组成、局部类固醇代谢和磷酸化。本文将评估这些机制在定义神经类固醇与突触和突触外GABA（A）受体的相互作用中的相对贡献。(C)2005年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Dysfunction of GABA(A) receptor-mediated inhibition is implicated in a number of neurological and psychiatric conditions including epilepsy and affective disorders. Some of these conditions have been associated with abnormal levels of certain endogenously occurring neurosteroids, which potently and selectively enhance the function of the brain's major inhibitory receptor, the GABA(A) receptor. Consistent with their ability to enhance neuronal inhibition, such steroids exhibit in animals and humans anxiolytic, anticonvulsant and anesthetic actions. Neurosteroids, exemplified by the potent progesterone metabolite, 5 alpha-pregnan-3 alpha-ol-20-one can be synthesized de novo in the CNS both in neurones and glia in levels sufficient to modulate GABA(A) receptor function. Neurosteroid levels are not static, but are subject to dynamic fluctuations, for example during stress, or the later stages of pregnancy. These observations suggest that these endogenous modulators may refine the function of the brain's major inhibitory receptor and thus, play an important physiological and pathophysiological role. However, given the ubiquitous expression of GABA(A) receptors throughout the mammalian CNS, changes in neurosteroid levels should be widely experienced, causing a generalized enhancement of neuronal inhibition. Such a non-specific action would seem incompatible with a physiological role. However, neurosteroid action is both brain region and neurone selective. This specificity results from a variety of molecular mechanisms including receptor subunit composition, local steroid metabolism and phosphorylation. This paper will evaluate the relative contribution these mechanisms play in defining the interaction of neurosteroids with synaptic and extra-synaptic GABA(A) receptors. (C) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.