科学家揭示甘氨酸受体门控和部分激活剂的工作机制
2021-02-11   阅读:426   来源:细胞

美国俄勒冈健康与科学大学Eric Gouaux和英国伦敦大学学院Lucia Sivilotti研究小组合作取得一项新突破。他们揭示了甘氨酸受体门控和部分激活剂的作用机制。该研究于2021年2月9日在线发表于国际学术期刊《细胞》。

研究人员探究了甘氨酸受体与完全激活剂甘氨酸受体和部分激活剂牛磺酸和γ-氨基丁酸(GABA)结合的功能。使用电生理学,研究人员探究了部分激活剂如何填充激活剂结合闭合通道的状态以及利用冷冻电镜重建阐明中间、开放前状态的结构,从而提供了沿受体反应途径先前未知的构象状态。

研究进一步将受体家族成员之间的开放通道概率(Po)激活剂诱导的构象变化相关联,为Cys-loop受体的部分和完全激活剂作用提供了一种可能的机制。

据悉,受体门控离子通道在化学突触中介导信号转导,并通过神经递质结合在静止、开放和脱敏状态之间转换。能产生最大Po的神经递质是完全激活剂,而产生低于最大Po的神经递质充当部分激活剂。半胱氨酸环受体是一类重要的神经递质受体,但对部分激活剂作用的结构基础仍亟待解决。

附:英文原文

Title: Mechanism of gating and partial agonist action in the glycine receptor

Author: Jie Yu, Hongtao Zhu, Remigijus Lape, Timo Greiner, Juan Du, Wei Lü, Lucia Sivilotti, Eric Gouaux

Issue&Volume: 2021-02-09

Abstract: Ligand-gated ion channels mediate signal transduction at chemical synapses and transitionbetween resting, open, and desensitized states in response to neurotransmitter binding.Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists,whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptorsare an important class of neurotransmitter receptors, yet a structure-based understandingof the mechanism of partial agonist action has proven elusive. Here, we study theglycine receptor with the full agonist glycine and the partial agonists taurine andγ-amino butyric acid (GABA). We use electrophysiology to show how partial agonistspopulate agonist-bound, closed channel states and cryo-EM reconstructions to illuminatethe structures of intermediate, pre-open states, providing insights into previouslyunseen conformational states along the receptor reaction pathway. We further correlateagonist-induced conformational changes to Po across members of the receptor family,providing a hypothetical mechanism for partial and full agonist action at Cys-loopreceptors.

DOI: 10.1016/j.cell.2021.01.026

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