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.

中文翻译：

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Apo状态和TARP化学计量的纳米级流动性决定了选择性剪接的AMPA受体的门控行为

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激动剂结合的激活通道上，而对载脂蛋白或静止状态的作用较小。在这里，我们表明，静止的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）的纳米级迁移性决定了对神经递质，变构阴离子和TARP辅助亚基的反应能力。静息的移动性通过配体结合域的触发器盒的可变剪接来调节，该可变体控制远处的AMPA受体N末端域（NTD）中的运动。翻转变体可促进NTD的缓慢运动，从而通过阴离子和辅助亚基建立较慢的通道脱敏作用和稳定的调节作用。相比之下，翻牌匣赋予的更大的NTD机动性充当主开关，以克服变构调节。在AMPA受体异聚体中，TARP化学计量进一步修饰了翻转/翻转盒的这些作用，产生了两种功能不同的部分和完全TARP受体，这是小脑星状细胞和Purkinje细胞的典型特征。