Neurochemistry

K2060: A Novel Open-Channel Blocker with Enhanced Membrane-to-Channel Inhibition for NMDAR Dysfunction. (A) Diagram illustrating enhanced membrane-to-channel inhibition of K2060 compared to memantine, with slower onset and offset of inhibition via the traditional pathway. (B) Table comparing key parameters of classical and membrane-to-channel inhibition, including the efficacy of inhibition via the classical and membrane-to-channel pathways, as well as the kinetics of the onset and offset of inhibition in the classical mechanism.

Mobility of NMDA receptor subunits using nanoprobes. (A) Schematic diagram depicting QD-based probes. The usual antiGFP-QD605 probe contains a large antibody and another antibody conjugated to QD605. The nanoGFP-QD605 probe contains a small nanobody directly conjugated to QD605. (B) Representative surface trajectories of GFP-GluN2A-containing, GFP-GluN2B-containing, or GFP-GluN3A-containing NMDARs (green) in hippocampal neurons expressing synaptic marker Homer (red) tracked using nanoprobe (colored trajectories). (C) Graph summarising the diffusion coefficient D values for nanoprobe trajectories, mobility of NMDA receptor subunits is as follows: GFP-GluN2A < GFP-GluN2B < GFP-GluN3A.

The pathogenic N650K variant in the GluN1 subunit regulates open probability of NMDA receptors and reduces NMDA-induced excitotoxicity. (A) Structural model of the M1, M2, and M3 domains in the hGluN1/hGluN2A heterotetramer; the residue studied here is indicated in red. (B) Single channel activity recordings in HEK293 cells expressing either GluN1/GluN2A (left) or GluN1-N650K/GluN2A (right) receptors (C) Representative images of YFP and Hoechst 33342 fluorescence in hippocampal neurons expressing YFP-tagged GluN1 or GluN1-N650K subunits. (D) Summary of the percentage of dead (i.e., pyknotic) neurons expressing the indicated hGluN1-1a subunits and treated with the indicated concentrations of NMDA.

Mutations in the M3 domain of GluN1 subunit differentially affect the sensitivity of NMDA receptors to memantine. (1, 2) Representative whole-cell recordings of primary hippocampal neurons (1) and normalized dose-response curves (2), obtained from experimental data, show a change in affinity to memantine in WT and mutant receptors. (3) After long-term exposure to high concentrations of NMDA, memantine significantly reduced excitotoxicity in neurons expressing GluN1 and GluN1-M641I subunits but not GluN1-A645S subunit. (4) Summary of the percentage of dead neurons expressing the indicated GluN1-1a subunits and treated with 30 μM memantine (Mem).