AMPA glutamate receptors (AMPARs) are ion channel tetramers that mediate the majority of fast excitatory synaptic transmission. They are composed of four subunits (GluA1–GluA4); the GluA2 subunit dominates AMPAR function throughout the forebrain. Its extracellular N-terminal domain (NTD) determines receptor localization at the synapse, ensuring reliable synaptic transmission and plasticity. This synaptic anchoring function requires a compact NTD tier, stabilized by a GluA2-specific NTD interface. Here we show that low pH conditions, which accompany synaptic activity, rupture this interface. All-atom molecular dynamics simulations reveal that protonation of an interfacial histidine residue (H208) centrally contributes to NTD rearrangement. Moreover, in stark contrast to their canonical compact arrangement at neutral pH, GluA2 cryo-electron microscopy structures exhibit a wide spectrum of NTD conformations under acidic conditions. We show that the consequences of this pH-dependent conformational control are twofold: rupture of the NTD tier slows recovery from desensitized states and increases receptor mobility at mouse hippocampal synapses. Therefore, a proton-triggered NTD switch will shape both AMPAR location and kinetics, thereby impacting synaptic signal transmission.

AMPA 谷氨酸受体 （AMPAR） 是离子通道四聚体，可介导大多数快速兴奋性突触传递。它们由四个亚基 （GluA1-GluA4） 组成;GluA2 亚基在整个前脑中主导 AMPAR 功能。其细胞外 N 末端结构域 （NTD） 决定了突触处的受体定位，确保可靠的突触传递和可塑性。这种突触锚定功能需要一个紧凑的 NTD 层，由 GluA2 特异性 NTD 界面稳定。在这里，我们表明伴随突触活动的低 pH 条件会破坏该界面。全原子分子动力学模拟表明，界面组氨酸残基 （H208） 的质子化主要有助于 NTD 重排。此外，与它们在中性 pH 下的经典紧凑排列形成鲜明对比的是，GluA2 冷冻电子显微镜结构在酸性条件下表现出广泛的 NTD 构象。我们表明，这种 pH 依赖性构象控制的后果是双重的：NTD 层的破裂减慢了从脱敏状态的恢复并增加了小鼠海马突触的受体迁移率。因此，质子触发的 NTD 开关将塑造 AMPAR 位置和动力学，从而影响突触信号传递。