Channel Receptors Unit, Institut Pasteur, CNRS UMR 3571, Paris, France.
J Physiol. 2018 May 15;596(10):1873-1902. doi: 10.1113/JP275100. Epub 2018 Apr 17.
Pentameric ligand-gated ion channels (pLGICs) mediate fast neurotransmission in the nervous system. Their dysfunction is associated with psychiatric, neurological and neurodegenerative disorders such as schizophrenia, epilepsy and Alzheimer's disease. Understanding their biophysical and pharmacological properties, at both the functional and the structural level, thus holds many therapeutic promises. In addition to their agonist-elicited activation, most pLGICs display another key allosteric property, namely desensitization, in which they enter a shut state refractory to activation upon sustained agonist binding. While the activation mechanisms of several pLGICs have been revealed at near-atomic resolution, the structural foundation of desensitization has long remained elusive. Recent structural and functional data now suggest that the activation and desensitization gates are distinct, and are located at both sides of the ion channel. Such a 'dual gate mechanism' accounts for the marked allosteric effects of channel blockers, a feature illustrated herein by theoretical kinetics simulations. Comparison with other classes of ligand- and voltage-gated ion channels shows that this dual gate mechanism emerges as a common theme for the desensitization and inactivation properties of structurally unrelated ion channels.
五聚体配体门控离子通道（pLGICs）在神经系统中介导快速神经传递。它们的功能障碍与精神疾病、神经疾病和神经退行性疾病有关，如精神分裂症、癫痫和阿尔茨海默病。因此，了解它们在功能和结构水平上的生物物理和药理学特性具有许多治疗前景。除了它们的激动剂引发的激活之外，大多数 pLGICs 还显示出另一个关键的变构特性，即脱敏，在持续的激动剂结合后，它们进入对激活无反应的关闭状态。虽然几种 pLGIC 的激活机制已经在近原子分辨率下揭示，但脱敏的结构基础长期以来一直难以捉摸。最近的结构和功能数据表明，激活和脱敏门是不同的，位于离子通道的两侧。这种“双门机制”解释了通道阻滞剂的显著变构效应，本文通过理论动力学模拟进行了说明。与其他配体门控和电压门控离子通道的比较表明，这种双门机制是结构上不相关的离子通道脱敏和失活特性的共同主题。
