1.A.10.1.20
Heteromeric ionotropic NMDA receptor (NMDAR) consisting of two subunits, GluN1 (938 aas) and GluN2A (1464 aas).  Positions of the Mg²⁺ and Ca²⁺ ions in the ion channel divalent cation binding site have been proposed, and differences in the structural and dynamic behavior of the channel proteins in the presence of Mg²⁺ or Ca²⁺ have been analyzed (Mesbahi-Vasey et al. 2017). GRIN variants in receptor M2 channel pore-forming loop are associated with neurological diseases (Li et al. 2019). Disease-associated variants have revealed mechanistic aspect of the NMDA receptor (Amin et al. 2021). Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors (Iacobucci et al. 2021). The gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors have been reported (Wang et al. 2021). GluN2A and GluN2B NMDA receptors apparently use distinct allosteric routes (Tian et al. 2021). A negative allosteric modulatory site in the GluN1 M4 determines the efficiency of neurosteroid modulation (Langer et al. 2021). Excitatory signaling mediated by NMDAR is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs can be used for treating depression, Alzheimer's disease, and epilepsy. Chou et al. 2022 monitored the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site. The channel blockers form interactions with pore-lining residues, which control mostly off-speeds but not on-speeds (Chou et al. 2022).  NMDAR channel blockers include MK-801, phencyclidine, ketamine, and the Alzheimer's disease drug memantine, can bind and unbind only when the NMDAR channel is open. NMDAR channel blockers can enter the channel through two routes: the well-known hydrophilic path from extracellular solution to channel through the open channel gate, and also a hydrophobic path from plasma membrane to channel through a gated fenestration (Wilcox et al. 2022). Pregnane-based steroids are  positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations (Kysilov et al. 2022). The NMDA receptor C-terminal domain signals in development, maturity, and disease (Haddow et al. 2022). Blood tissue Plasminogen Activator (tPA) of liver origin contributes to neurovascular coupling involving brain endothelial N-Methyl-D-Aspartate (NMDA) receptors (Furon et al. 2023). Two gates mediate NMDA receptor activity and are under subunit-specific regulation (Amin et al. 2023). One of the main molecular mechanisms of ketamine action is the blockage of NMDA-activated glutamate receptors (Pochwat 2022). The S1-M1 linker of the NMDA receptor controls channel opening (Xie et al. 2023). Binding and dynamics demonstrated the destabilization of ligand binding for the S688Y mutation in the NMDA receptor GluN1 subunit (Chen et al. 2023). The functional effects of disease-associated NMDA receptor variants have been reviewed (Moody et al. 2023). Co-activation of NMDAR and mGluRs controls protein nanoparticle-induced osmotic pressure in neurotoxic edema (Zheng et al. 2023).  Disease-associated nonsense and frame-shift variants resulting in the truncation of the GluN2A or GluN2B C-terminal domain decreases NMDAR surface expression and reduces potentiating effects of neurosteroids (Kysilov et al. 2024).  De novo GRIN variants in the M3 helix associated with neurological disorders control channel gating of the NMDA receptor (Xu et al. 2024).  Ketamine is a rapid and potent antidepressant.  Ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons (Chen et al. 2024). This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine's antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus (Chen et al. 2024). NMDA receptor-modulating treatments for cognitive and plasticity deficits in schizophreniahave been studied (Sehatpour and Kantrowitz 2025).  Patient-derived NMDAR mAbs combined with single-particle cryo-EM reveal multiple GluN1 epitopes and distinct functional effects (Spatola and Dalmau 2025).  The N-methyl-D-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands, glutamate and glycine, for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively (Chou et al. 2024).  Positive allosteric modulators have been identified (Li et al. 2025).