Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat neuropsychiatric and neurological disorders, including epilepsy. Here we present cryogenic-electron microscopy structures of rat GluA2 AMPAR complexes with inhibitory mouse γ5 and potentiating human cornichon-2 (CNIH2) auxiliary subunits. CNIH2 appears to destabilize the desensitized state of the complex by reducing the separation of the upper lobes in ligand-binding domain dimers. At the same time, CNIH2 stabilizes binding of polyamine spermidine to the selectivity filter of the closed ion channel. Nevertheless, CNIH2, and to a lesser extent γ5, attenuate polyamine block of the open channel and reduce the potency of the antiepileptic drug perampanel that inhibits the synaptic complex allosterically by binding to sites in the ion channel extracellular collar. These findings illustrate the fine-tuning of synaptic complex structure and function in an auxiliary subunit-dependent manner, which is critical for the study of brain region-specific neurotransmission and design of therapeutics for disease treatment.

α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体 (AMPAR) 与辅助亚基的突触复合物介导大多数兴奋性神经传递，可用于治疗神经精神和神经系统疾病，包括癫痫。在这里，我们展示了大鼠 GluA2 AMPAR 复合物与抑制性小鼠 γ5 和增强人 cornichon-2 (CNIH2) 辅助亚基的低温电子显微镜结构。 CNIH2 似乎通过减少配体结合域二聚体上叶的分离来破坏复合物的脱敏状态。同时，CNIH2 稳定聚胺亚精胺与封闭离子通道的选择性过滤器的结合。然而，CNIH2 以及较小程度的 γ5 减弱了开放通道的多胺阻断，并降低了抗癫痫药物吡仑帕奈的效力，吡仑帕奈通过与离子通道细胞外领中的位点结合来变构抑制突触复合体。这些发现说明了突触复杂结构和功能以辅助亚基依赖性方式进行微调，这对于研究大脑区域特异性神经传递和疾病治疗疗法的设计至关重要。