Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
Department of Neuroscience, Physiology and Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK.
Cell. 2021 Feb 18;184(4):957-968.e21. doi: 10.1016/j.cell.2021.01.026. Epub 2021 Feb 9.
Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between 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 receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Here, we study the glycine receptor with the full agonist glycine and the partial agonists taurine and γ-amino butyric acid (GABA). We use electrophysiology to show how partial agonists populate agonist-bound, closed channel states and cryo-EM reconstructions to illuminate the structures of intermediate, pre-open states, providing insights into previously unseen conformational states along the receptor reaction pathway. We further correlate agonist-induced conformational changes to Po across members of the receptor family, providing a hypothetical mechanism for partial and full agonist action at Cys-loop receptors.
配体门控离子通道在化学突触中介导信号转导，并在响应神经递质结合时在静息、开放和脱敏状态之间转换。产生最大开放通道概率 (Po) 的神经递质是完全激动剂，而产生低于最大 Po 的神经递质是部分激动剂。Cys 环受体是一类重要的神经递质受体，但基于结构的部分激动剂作用机制一直难以捉摸。在这里，我们研究了甘氨酸受体与完全激动剂甘氨酸以及部分激动剂牛磺酸和 γ-氨基丁酸 (GABA)。我们使用电生理学来展示部分激动剂如何填充激动剂结合的关闭通道状态，并用冷冻电镜重建来阐明中间预开放状态的结构，从而深入了解受体反应途径中以前看不见的构象状态。我们进一步将激动剂诱导的构象变化与受体家族成员的 Po 相关联，为 Cys 环受体的部分和完全激动剂作用提供了一个假设机制。
