Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of GluN1 and GluN2 subunits, which bind glycine and glutamate, respectively, to activate their ion channels. Despite importance in brain physiology, the precise mechanisms by which activation and inhibition occur via subunit-specific binding of agonists and antagonists remain largely unknown. Here, we show the detailed patterns of conformational changes and inter-subunit and -domain reorientation leading to agonist-gating and subunit-dependent competitive inhibition by providing multiple structures in distinct ligand states at 4 Å or better. The structures reveal that activation and competitive inhibition by both GluN1 and GluN2 antagonists occur by controlling the tension of the linker between the ligand-binding domain and the transmembrane ion channel of the GluN2 subunit. Our results provide detailed mechanistic insights into NMDAR pharmacology, activation, and inhibition, which are fundamental to the brain physiology.

由包括N-甲基-D-天冬氨酸受体 (NMDAR)在内的谷氨酸受体介导的兴奋性神经传递对于大脑发育和功能至关重要。NMDAR 是由 GluN1 和 GluN2 亚基组成的异四聚体，分别结合甘氨酸和谷氨酸以激活其离子通道。尽管在脑生理学中很重要，但通过激动剂和拮抗剂的亚基特异性结合发生激活和抑制的精确机制仍然很大程度上未知。在这里，我们通过提供 4 Å 或更好的不同配体状态的多个结构，展示了构象变化以及亚基间和结构域重新定向的详细模式，从而导致激动剂门控和亚基依赖性竞争性抑制。该结构揭示了 GluN1 和 GluN2 拮抗剂的激活和竞争性抑制是通过控制配体结合域和 GluN2 亚基跨膜离子通道之间的连接体的张力而发生的。我们的研究结果为 NMDAR 药理学、激活和抑制提供了详细的机制见解，这对大脑生理学至关重要。