State-specific inhibition of NMDA receptors by memantine depends on intracellular calcium and provides insights into NMDAR channel blocker tolerability

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.