Structural basis of ketamine action on human NMDA receptors

Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers

“…As the above data indicate that the inability of ketamine to rescue of GluN2A-P552R mediated dendrotoxicity is not due to a loss of potency or innate toxicity, we next aimed to determine whether memantine's ability to rescue this phenotype was through its classically defined role as an NMDA receptor channel antagonist or through an undefined, alternative mechanism. To this end, we exposed GluN2A-P55R expressing neurons to the open-channel blocker MK-801, which binds to the same pocket of the NMDAR as memantine and ketamine (Song et al, 2018;Zhang et al, 2021). Treatment with 10 µM MK-801 similarly abolished GluN2A-P552R mediated dendritic blebbing (One-way ANOVA, p > 0.05) (Figures 3A,B), strongly suggesting that memantine rescues GluN2A-P552R through its known mechanism of pharmacological action.…”

“…However, memantine binds to the pore by interacting with the amino acids that cluster around the area of this mutation (N612, N613, and N614) (Song et al, 2018), while dextromethorphan is thought to interact with residues in a more extracellular portion of the vestibule (LePage et al, 2005). Thus, increased inhibition of GluN2A-N615K containing receptors by dextromethorphan is consistent with the understanding of its binding site, while differences in binding sites cannot explain the observed differential dendroprotective response of GluN2A-P552R-containing NMDA receptors to memantine and ketamine, as these channel blockers bind to an overlapping site in the pore (Emnett et al, 2013;Zhang et al, 2021). To account for the noted changes, we explored whether memantine and ketamine differentially activate or inhibit kinases downstream of neurotoxic NMDAR signaling.…”

“…GluN2A-P552R-mediated dendrotoxicity was attenuated by treatment with 50 µM memantine (One-way ANOVA, p 0.3025, n 9) (Figures 1A,C), as previously shown, confirming that FDAapproved NMDAR antagonists may be a viable treatment strategy for individual(s) with this mutation. Surprisingly, although ketamine and memantine share the same mechanism of action, similar pharmacodynamic profiles, and overlapping binding sites within NMDA receptors (Song et al, 2018;Zhang et al, 2021;Emnett et al, 2013), we found that ketamine treatment did not rescue GluN2A-P552R mediated dendritic blebbing (One-way ANOVA, p < 0.0001; Multiple comparisons, pCI-neo vs. GluN2A, p 0.9407, pCI-neo vs. GluN2A-P552R, p < 0.0001, GluN2A vs. GluN2A-P552R, p < 0.0001, n 9) (Figures 2A,B). Indeed, an unpaired t-test revealed that there was no difference in the number of dendritic blebs per coverslip between untreated neurons and those treated with 50 µM ketamine (p 0.7819, n 9).…”

N-Methyl-d-aspartic Acid (NMDA) Receptor Is Involved in the Inhibitory Effect of Ketamine on Human Sperm Functions

“…Among them, NMDAR2A and NMDAR2B had the highest expression in the testis. Moreover, NMDAR2A and NMDAR2B are the most abundant in mammals [9]. Therefore, Western blot analysis was first performed on proteins from freshly collected human sperm to further confirm the expression of the NMDA receptor in human sperm.…”

Editorial: Ion Channels: Therapeutic Targets for Neurological Disease

“…Lee and Zhou also discussed limitations of these animal models and their potential utility for therapeutic applications. With the recent breakthrough on structural and pharmacological studies of NMDAR (Zhang et al, 2021 ), these animal models will provide useful platforms to identify novel therapeutics for schizophrenia.…”