AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning¹. A diverse array of AMPAR signalling complexes are established by receptor auxiliary subunits, which associate with the AMPAR in various combinations to modulate trafficking, gating and synaptic strength². However, their mechanisms of action are poorly understood. Here we determine cryo-electron microscopy structures of the heteromeric GluA1–GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR complex in the forebrain, in both resting and active states. Two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of the receptor, with site-specific lipids shaping each interaction and affecting the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry between GluA1 and GluA2 along the ion conduction path and an outward expansion of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards the pore exit upon activation, extending their reach for cytoplasmic receptor elements. CNIH2 achieves this through its uniquely extended M2 helix, which has transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator that is capable of providing hippocampal pyramidal neurons with their integrative synaptic properties.

AMPA 受体 (AMPAR) 介导大脑中的大部分兴奋性传递，并使构成学习基础的突触可塑性成为可能¹。受体辅助亚基建立了一系列不同的 AMPAR 信号复合物，这些亚基以各种组合与 AMPAR 结合以调节运输、门控和突触强度². 然而，人们对它们的作用机制知之甚少。在这里，我们确定了与 TARP-γ8 和 CNIH2（前脑中主要的 AMPAR 复合体）组装的异聚 GluA1-GluA2 受体在静息和活动状态下的冷冻电子显微镜结构。两个 TARP-γ8 和两个 CNIH2 亚基插入受体配体结合域下方的不同位点，位点特异性脂质塑造每个相互作用并影响 AMPAR 的门控调节。受体的激活导致 GluA1 和 GluA2 沿离子传导路径的不对称，通道的向外扩张触发两个辅助亚基对的反向旋转，促进活性状态构象。此外，TARP-γ8 和 CNIH2 在激活后都转向孔出口，扩大它们对细胞质受体元件的影响。CNIH2 通过其独特的扩展 M2 螺旋实现了这一点，该螺旋将这种内质网输出因子转化为强大的 AMPAR 调节剂，能够为海马锥体神经元提供其整合的突触特性。