Differential responses of disease‐related GRIN variants located in pore‐forming M2 domain of N‐methyl‐D‐aspartate receptor to FDA‐approved inhibitors

N‐methyl‐D‐aspartate receptors (NMDAR), ionotropic glutamate receptors, mediate a slow component of excitatory synaptic transmission in the central nervous system and play a key role in normal brain function and development. Genetic variations in GRIN genes encoding NMDAR subunits that alter the receptor's functional characteristics are associated with a wide range of neurological and neuropsychiatric conditions. Pathological GRIN variants located in the M2 re‐entrant loop lining the channel pore cause significant functional changes, the most consequential alteration being a reduction in voltage‐dependent Mg2+ inhibition. Voltage‐dependent Mg2+ block is a unique feature of NMDAR biology whereby channel activation requires both ligand binding and postsynaptic membrane depolarization. Thus, loss of NMDAR Mg2+ block will have a profound impact on synaptic function and plasticity. Here, we choose 11 missense variants within the GRIN1, GRIN2A, and GRIN2B genes that alter residues located in the M2 loop and significantly reduce Mg2+ inhibition. Each variant was evaluated for tolerance to genetic variation using the 3‐dimensional structure and assessed for functional rescue pharmacology via electrophysiological recordings. Three FDA‐approved NMDAR drugs—memantine, dextromethorphan, and ketamine—were chosen based on their ability to bind near the M2 re‐entrant loop, potentially rectifying dysregulated NMDAR function by supplementing the reduced voltage‐dependent Mg2+ block. These results provide insight of structural determinants of FDA‐approved NMDAR drugs at their binding sites in the channel pore and may further define conditions necessary for the use of such agents as potential rescue pharmacology. Eleven disease‐related missense variants in GRIN1, GRIN2A, and GRIN2B genes located in the pore‐forming M2 re‐entrant loop were evaluated for tolerance to genetic variation using three‐dimensional structure and assessed for functional rescue pharmacology via electrophysiology. Three FDA‐approved N‐methyl‐D‐aspartate receptors (NMDAR) drugs (memantine, dextromethorphan, ketamine) were chosen based on their ability to bind near the M2 loop, potentially rectifying dysregulated NMDAR function by supplementing the reduced voltage‐dependent Mg2+ block. These results provide insight into the structural determinants of FDA‐approved NMDAR drugs at their binding sites in the channel pore and may further define conditions necessary for the use of such agents as potential rescu