Synaptic GABA_A receptors are alternately exposed to short pulses of a high, millimolar concentration of GABA and prolonged periods of low, micromolar concentration of the transmitter. Prior work has indicated that exposure to micromolar concentrations of GABA can both activate the postsynaptic receptors generating sustained low-amplitude current and desensitize the receptors, thereby reducing the peak amplitude of subsequent synaptic response. However, the precise relationship between tonic activation and reduction of peak response is not known. Here, we have measured the effect of prolonged exposure to GABA or the combination of GABA and the neurosteroid allopregnanolone, which was intended to desensitize a fraction of receptors, on a subsequent response to a high concentration of agonist in human α1β3γ2L receptors expressed in Xenopus oocytes. We show that the reduction in the peak amplitude of the post-exposure test response correlates with the open probability of the preceding desensitizing response. Curve fitting of the inhibitory relationship yielded an IC₅₀ of 12.5 µM and a Hill coefficient of −1.61. The activation and desensitization data were mechanistically analyzed in the framework of a three-state Resting-Active-Desensitized model. Using the estimated affinity, efficacy, and desensitization parameters, we calculated the amount of desensitization that would accumulate during a long (2-minute) application of GABA or GABA plus allopregnanolone. The results indicate that accumulation of desensitization depends on the level of activity rather than agonist or potentiator concentration per se. We estimate that in the presence of 1 µM GABA, approximately 5% of α1β3γ2L receptors are functionally eliminated because of desensitization.

中文翻译：

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长时间暴露于低浓度激动剂后突触型 GABAA 受体的激活降低：强直活动与脱敏之间的关系

突触 GABA _A受体交替暴露于高、毫摩尔浓度的 GABA 短脉冲和长时间的低、微摩尔浓度的递质。先前的工作表明，暴露于微摩尔浓度的 GABA 可以激活突触后受体，产生持续的低振幅电流并使受体脱敏，从而降低后续突触反应的峰值振幅。然而，强直激活和峰值响应降低之间的确切关系尚不清楚。在这里，我们测量了长期暴露于 GABA 或 GABA 与神经甾体别孕烯醇酮的组合对人体对高浓度激动剂的后续反应的影响，后者旨在使一部分受体脱敏。α 1 β 3 γ 2L 受体在非洲爪蟾卵母细胞中表达。我们表明，暴露后测试响应峰值幅度的降低与先前脱敏响应的开放概率相关。抑制关系的曲线拟合产生了 IC ₅₀12.5 µM 和 -1.61 的希尔系数。在三态静息-主动-脱敏模型的框架内对活化和脱敏数据进行了机械分析。使用估计的亲和力、功效和脱敏参数，我们计算了在长时间（2 分钟）应用 GABA 或 GABA 加别孕酮期间会积累的脱敏量。结果表明，脱敏作用的积累取决于活性水平，而不是激动剂或增效剂浓度本身。我们估计在 1 µM GABA 的存在下，由于脱敏，大约 5% 的α 1 β 3 γ 2L 受体在功能上被消除。