Extracellular Ca(2+) ions reduce NMDA receptor conductance and gating.

Brief intracellular Ca(2+) transients initiate signaling routines that direct cellular activities. Consequently, activation of Ca(2+)-permeable neurotransmitter-gated channels can both depolarize and initiate remodeling of the postsynaptic cell. In particular, the Ca(2+) transient produced by NMDA receptors is essential to normal synaptic physiology, drives the development and plasticity of excitatory central synapses, and also mediates glutamate excitotoxicity. The amplitude and time course of the Ca(2+) signal depends on the receptor's conductance and gating kinetics; these properties are themselves influenced both directly and indirectly by fluctuations in the extracellular Ca(2+) concentration. Here, we used electrophysiology and kinetic modeling to delineate the direct effects of extracellular Ca(2+) on recombinant GluN1/GluN2A receptor conductance and gating. We report that, in addition to decreasing unitary conductance, Ca(2+) also decreased channel open probability primarily by lengthening closed-channel periods. Using one-channel current recordings, we derive a kinetic model for GluN1/GluN2A receptors in physiological Ca(2+) concentrations that accurately describes macroscopic channel behaviors. This model represents a practical instrument to probe the mechanisms that control the Ca(2+) transients produced by NMDA receptors during both normal and aberrant synaptic signaling.