Integrated Program in Neuroscience, McGill University, Montréal, QC H3A 2B4, Canada; Department of Pharmacology and Therapeutics, McGill University, Montréal, QC H3G 1Y6, Canada.
Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Neuron. 2019 Jun 5;102(5):976-992.e5. doi: 10.1016/j.neuron.2019.03.046. Epub 2019 Apr 30.
Neurotransmitter-gated ion channels are allosteric proteins that switch on and off in response to agonist binding. Most studies have focused on the agonist-bound, activated channel while assigning a lesser role to the apo or resting state. Here, we show that nanoscale mobility of resting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (AMPA receptors) predetermines responsiveness to neurotransmitter, allosteric anions and TARP auxiliary subunits. Mobility at rest is regulated by alternative splicing of the flip/flop cassette of the ligand-binding domain, which controls motions in the distant AMPA receptor N-terminal domain (NTD). Flip variants promote moderate NTD movement, which establishes slower channel desensitization and robust regulation by anions and auxiliary subunits. In contrast, greater NTD mobility imparted by the flop cassette acts as a master switch to override allosteric regulation. In AMPA receptor heteromers, TARP stoichiometry further modifies these actions of the flip/flop cassette generating two functionally distinct classes of partially and fully TARPed receptors typical of cerebellar stellate and Purkinje cells.
神经递质门控离子通道是变构蛋白，可响应激动剂结合而开启和关闭。大多数研究都集中在与激动剂结合的激活状态的通道上，而对apo 或静息状态的通道作用较小。在这里，我们表明，静息状态下的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型离子型谷氨酸受体（AMPA 受体）的纳米级迁移率预先决定了对神经递质、变构阴离子和 TARP 辅助亚基的反应性。在休息时的流动性由配体结合域的翻转/翻转盒的选择性剪接调节，该剪接控制 AMPA 受体 N 端结构域（NTD）中的远距离运动。翻转变体促进适度的 NTD 运动，从而建立较慢的通道脱敏作用，并通过阴离子和辅助亚基进行强大的调节。相比之下，由翻转盒赋予的更大的 NTD 迁移率充当主开关，以覆盖变构调节。在 AMPA 受体异聚体中，TARP 计量进一步修饰了翻转/翻转盒的这些作用，产生了两种功能上不同的部分和完全 TARPed 受体类别，这些受体是小脑星状细胞和浦肯野细胞的典型特征。
