State-specific inhibition of NMDA receptors by memantine provides insight into NMDAR channel blocker tolerability
- 1Department of Neuroscience and Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
- 2Department of Neurobiology and the Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- 3Department of Pharmacology, University of California, Davis, CA, USA
Abstract
NMDA receptors (NMDARs) are key mediators of neuronal Ca 2+ influx. NMDAR-mediated Ca 2+ influx plays a central role in synaptogenesis, synaptic plasticity, dendritic integration, and neuronal survival. However, excessive NMDAR-mediated Ca 2+ influx initiates cellular signaling pathways that result in neuronal death and is broadly associated with neurological disease. Drugs targeting NMDARs are of great clinical interest, but widespread alteration of NMDAR activity can generate negative side effects. The NMDAR channel blocker memantine is a well-tolerated Alzheimer’s disease medication that shows promise in treatment of other neurological disorders. Memantine enhances desensitization of NMDARs in a subtype- and Ca 2+ -dependent manner, thereby more effectively inhibiting NMDARs on neurons that experience increased buildup of intracellular Ca 2+ . However, little is known about the properties or implications of the interaction between intracellular Ca 2+ and NMDAR inhibition by memantine or other NMDAR channel blockers. Utilizing customized Ca 2+ buffering solutions and whole-cell patch-clamp recordings, we demonstrated that memantine inhibition of both recombinant and native NMDARs increases with increasing intracellular Ca 2+ and that the effect of intracellular Ca 2+ on memantine action depends on NMDAR subtype. Neuroprotection assays and recordings of postsynaptic currents revealed that memantine preferentially inhibits NMDARs under neurotoxic conditions whereas ketamine, a clinically useful NMDAR channel blocker with strong side effects, inhibits strongly across contexts. Our results present a previously unexamined form of state-specific antagonism, Ca 2+ -dependent NMDAR channel block, that could have a profound impact on the design of drugs that selectively target NMDAR subpopulations involved in disease.
Related
- Dizocilpine-derived K2060 exhibits enhanced blockage at NMDA receptors with impaired Mg2+ block and provides strong protection against audiogenic seizures
- Block of Thalamic 5-HT2A Receptors modulates Tonic GABA-A Inhibition but not Absence Seizures
- TOC159 receptors use a galactolipid-specific bipartite signal for chloroplast targeting in Arabidopsis thaliana
- CellMethMarker provides an integrated database of human cell- and tissue-type-specific DNA methylation markers
- Dual kinase inhibition provides early clues to restoration of neuroimmune homeostasis in an AAV-haSyn model of Parkinsons disease
BibTeX
@article{phillips2026statespecific,
title = {{State-specific inhibition of NMDA receptors by memantine provides insight into NMDAR channel blocker tolerability}},
author = {Matthew B. Phillips and Nadya V. Povysheva and Elizabeth G. Neureiter and Aparna Nigam and Karen A. Hartnett and Johannes W. Hell and Elias Aizenman and Jon W. Johnson},
journal = {Science Advances},
year = {2026},
month = may,
doi = {10.1126/sciadv.aec3154},
url = {https://doi.org/10.1126/sciadv.aec3154},
note = {CC BY},
}
RIS
TY - JOUR
TI - State-specific inhibition of NMDA receptors by memantine provides insight into NMDAR channel blocker tolerability
AU - Matthew B. Phillips
AU - Nadya V. Povysheva
AU - Elizabeth G. Neureiter
AU - Aparna Nigam
AU - Karen A. Hartnett
AU - Johannes W. Hell
AU - Elias Aizenman
AU - Jon W. Johnson
PY - 2026
DA - 2026/05/27
JO - Science Advances
DO - 10.1126/sciadv.aec3154
UR - https://doi.org/10.1126/sciadv.aec3154
AB - NMDA receptors (NMDARs) are key mediators of neuronal Ca 2+ influx. NMDAR-mediated Ca 2+ influx plays a central role in synaptogenesis, synaptic plasticity, dendritic integration, and neuronal survival. However, excessive NMDAR-mediated Ca 2+ influx initiates cellular signaling pathways that result in neuronal death and is broadly associated with neurological disease. Drugs targeting NMDARs are of great clinical interest, but widespread alteration of NMDAR activity can generate negative side effects. The NMDAR channel blocker memantine is a well-tolerated Alzheimer’s disease medication that shows promise in treatment of other neurological disorders. Memantine enhances desensitization of NMDARs in a subtype- and Ca 2+ -dependent manner, thereby more effectively inhibiting NMDARs on neurons that experience increased buildup of intracellular Ca 2+ . However, little is known about the properties or implications of the interaction between intracellular Ca 2+ and NMDAR inhibition by memantine or other NMDAR channel blockers. Utilizing customized Ca 2+ buffering solutions and whole-cell patch-clamp recordings, we demonstrated that memantine inhibition of both recombinant and native NMDARs increases with increasing intracellular Ca 2+ and that the effect of intracellular Ca 2+ on memantine action depends on NMDAR subtype. Neuroprotection assays and recordings of postsynaptic currents revealed that memantine preferentially inhibits NMDARs under neurotoxic conditions whereas ketamine, a clinically useful NMDAR channel blocker with strong side effects, inhibits strongly across contexts. Our results present a previously unexamined form of state-specific antagonism, Ca 2+ -dependent NMDAR channel block, that could have a profound impact on the design of drugs that selectively target NMDAR subpopulations involved in disease.
SN - 2375-2548
ER -