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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >A mutant residue in the third transmembrane region of the GABAA alphal subunit causes increased agonistic neurosteroid responses
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A mutant residue in the third transmembrane region of the GABAA alphal subunit causes increased agonistic neurosteroid responses

机译：GABAA alpha1亚基的第三个跨膜区域中的突变残基导致激动性神经甾体反应增加

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摘要

Pregnane derived steroids have agonistic and antagonistic actions at GABA_A receptors. Putative binding sites for agonistic neurosteroids are located within the transmembrane (TM) regions. A mutation within the rat alpha_1 TM3 region, S299C, caused the expressed receptors to have unusual and extreme sensitivity to agonistic neurosteroids. For mutant alS299C receptors, with wild type 3 and y subunits, expressed in Xenopus oocytes, steroids activated the GABA_A receptors in the absence of GABA. Maximal steroid induced currents were about half of maximal GABA currents. The steroid activation was biphasic with EC_(50)'s much lower than wild type, in subnanomolar and nanomolar concentrations, while the wild type had only one activation peak with near micromolar EC_(50). These currents could be blocked by both picrotoxin and an antagonist neurosteroid. The steroids did not seem to potentiate significantly submaximal GABA currents. The a1 S299C mutation did not affect responses to the extracellularly acting partial agonist piperidine-4-sulfate. Substituted cysteine experiments indicate that this mutant can be modified by pCMBS" when the sulfhydryl reagent is added with the higher steroid concentration for activation but not the lower steroid concentration. The pCMBS~ will also immediately block the high concentration steroid current. Taken together the data suggest that al S299 is important in at least the in transduction of the steroid binding to the rest of the receptor.
机译：孕烷衍生的类固醇对GABA_A受体具有激动作用和拮抗作用。激动性神经类固醇的推定结合位点位于跨膜（TM）区域内。大鼠alpha_1 TM3区域内的一个突变S299C导致表达的受体对激动性神经类固醇具有异常和极端的敏感性。对于在非洲爪蟾卵母细胞中表达的具有野生型3和y亚基的突变型alS299C受体，类固醇可在不存在GABA的情况下激活GABA_A受体。类固醇诱导的最大电流约为最大GABA电流的一半。在亚纳摩尔和纳摩尔浓度下，类固醇的激活是双相的，EC_（50）远低于野生型，而野生型只有一个激活峰，接近微摩尔EC_（50）。这些电流可能被微毒素和拮抗剂神经甾体阻断。类固醇似乎并未显着增强最大的GABA电流。 a1 S299C突变不影响对细胞外作用的部分激动剂哌啶-4-硫酸盐的反应。替代的半胱氨酸实验表明，当添加巯基试剂以较高的类固醇浓度激活而不是较低的类固醇浓度时，该突变体可以被pCMBS修饰。pCMBS〜也将立即阻止高浓度的类固醇电流。综合数据提示，S299至少在类固醇与受体其余部分的结合的转导中很重要。

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