A quantitative description of NMDA receptor-channel kinetic behavior.

Currents evoked in neurons of the vertebrate CNS by the glutamate agonist N-methyl-D-aspartate (NMDA) exhibit a marked voltage dependence in the presence of extracellular Mg. At the single-channel level, the addition of external Mg alters single-channel openings from long-lived events to many very short events grouped into bursts of openings. These bursts apparently result from short interruptions of current flow during periods when the channel is in the open configuration. Single-channel currents evoked by NMDA have been studied in outside-out patches of membrane taken from hippocampal CA 1 neurons grown in dissociated cell culture. The effects of changing external Mg concentration and holding potential on the single-channel parameters of open time, closed time, and burst length have been successfully described assuming a 3- or 4-state model with 1 open state, 1 or 2 "blocked" states, and 1 absorbing closed state. Evaluation of the blocking rates over Mg concentrations from 0.2-200 microM indicate that a single "blocking" mechanism cannot account for the short closed states and that a second voltage-dependent but Mg-independent "blocked" state is necessary to explain the data especially at low Mg concentrations.