Abstract

N-Methyl-d-aspartate (NMDA) receptors are glutamate-gated ion channels with complex participation in synaptic transmission, integration, and plasticity. They are highly permeable to Ca²⁺, activate with characteristic kinetics, and generate currents with distinct amplitudes according to stimulation frequency. Multiple endogenous and pharmacological agents bind at distinct locations throughout the protein and modulate NMDA receptor responses with allosteric mechanisms. The NMDA receptor activation pathway consists of a series of consecutive, stepwise structural rearrangements rather than a binary, closed-open reaction. This high-resolution multistate gating reaction is used here to investigate the effects of ideal, state-specific modulators on physiologically relevant parameters of the macroscopic responses to single-pulse and high-frequency repetitive stimulation. The simulations suggest three significant aspects of NMDA receptor modulation: 1) modest, 1 kcal/mol bidirectional perturbations in receptor free energy cause up to a 50-fold change in the total charge transferred; 2) activators modulate primarily the response time course, whereas inhibitors are more effectively modulating current peak amplitude; and 3) state-specific modulators have opposite effects on charge transfer and current potentiation by high-frequency stimulation. The results imply that the magnitude of the NMDA receptor-mediated Ca²⁺ influx and the receptor's ability to discriminate stimulation frequency can be controlled separately. Thus, a detailed mechanistic characterization of NMDA receptor allosteric effectors may identify function-specific modulators and provides a road map for the development of combinatorial strategies for local, transient tuning of specific receptor functions.