Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA.
Trends Neurosci. 2010 Jul;33(7):299-306. doi: 10.1016/j.tins.2010.03.005. Epub 2010 Apr 19.
Endogenous neurosteroids and their synthetic analogs (neuroactive steroids) are potent modulators of GABA(A) receptors. Thus, they are of physiological and clinical relevance for their ability to modulate inhibitory function in the CNS. Despite their importance, fundamental issues of neurosteroid actions remain unresolved. Recent evidence suggests that glutamatergic principal neurons, rather than glia, are the major sources of neurosteroid synthesis. Other recent studies have identified putative neurosteroid binding sites on GABA(A) receptors. In this Opinion, we argue that neurosteroids require a membranous route of access to transmembrane-domain binding sites within GABA(A) receptors. This has implications for the design of future neuroactive steroids because the lipid solubility and related accessibility properties of the ligand are likely to be key determinants of receptor modulation.
内源性神经甾体及其合成类似物（神经活性甾体）是 GABA(A) 受体的有效调节剂。因此，它们具有调节中枢神经系统抑制功能的能力，具有生理和临床意义。尽管它们很重要，但神经甾体作用的一些基本问题仍未解决。最近的证据表明，谷氨酸能主神经元而不是神经胶质细胞是神经甾体合成的主要来源。其他最近的研究已经确定了 GABA(A) 受体上的推定神经甾体结合位点。在本观点中，我们认为神经甾体需要通过膜途径才能进入 GABA(A) 受体的跨膜结构域结合位点。这对未来神经活性甾体的设计具有重要意义，因为配体的脂溶性和相关可及性特性可能是受体调节的关键决定因素。
