Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors

Significance NMDA receptors are glutamatergic channels whose activation controls the strength of excitatory synapses in the central nervous system. Agonist binding initiates a complex activation reaction that consists of a stepwise sequence of reversible isomerizations. In addition to previously identified steps in this series, which include agonist-induced closure of the ligand-binding lobes and the subsequent mechanical pulling by the ligand-binding domain on the gate-forming transmembrane helix, we identify a cross-subunit interaction that stabilizes open receptors and slows the rate of the current decay. Naturally occurring NMDA receptor variants lacking this interaction are pathogenic.