Mechanism of gating and partial agonist action in the glycine receptor
Mechanism of gating and partial agonist action in the glycine receptor
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DOI：
10.1101/786632
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发表时间：
2019-09
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通讯作者：
Jie Yu;Hongtao Zhu;R. Lape;T. Greiner;Rezvan Shahoei;Yuhang Wang;Juan Du;Wei Lü;Emad Tajkhorsh
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作者：
Jie Yu;Hongtao Zhu;R. Lape;T. Greiner;Rezvan Shahoei;Yuhang Wang;Juan Du;Wei Lü;Emad Tajkhorsh
甘氨酸受体是一种五聚体、神经递质激活的离子通道，在关闭/休息、开放和脱敏状态之间转换。甘氨酸是一种完全激动剂，其开放通道概率(Po)为∼1.0，而部分激动剂，如牛磺酸和γ-氨基丁酸，则产生次最大Po值。尽管对五聚体Cys-loop受体进行了广泛的研究，但对部分激动剂作用的分子机制以及受体如何从闭合构象到开放构象和不敏感构象的转变知之甚少。在这里，我们使用电生理学和分子动力学(MD)模拟，结合大量的单粒子低温EM重建，来展示激动剂如何填充激动剂结合但关闭的通道状态，从而解释它们较低的效率，但也填充激动剂结合的开放和不敏感状态。神经递质结合袋内的测量作为结合激动剂的函数，提供了一个指标来将激动剂诱导的构象变化的程度与整个Cys-loop受体家族的开放通道概率相关联。
The glycine receptor is a pentameric, neurotransmitter-activated ion channel that transitions between closed/resting, open and desensitized states. Glycine, a full agonist, produces an open channel probability (Po) of ∼1.0 while partial agonists, such as taurine and γ-amino butyric acid (GABA) yield submaximal Po values. Despite extensive studies of pentameric Cys-loop receptors, there is little knowledge of the molecular mechanisms underpinning partial agonist action and how the receptor transitions from the closed to open and to desensitized conformations. Here we use electrophysiology and molecular dynamics (MD) simulations, together with a large ensemble of single particle cryo-EM reconstructions, to show how agonists populate agonist-bound yet closed channel states, thus explaining their lesser efficacy, yet also populate agonist-bound open and desensitized states. Measurements within the neurotransmitter binding pocket, as a function of bound agonist, provide a metric to correlate the extent of agonist-induced conformational changes to open channel probability across the Cys-loop receptor family.