Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics

The conductance activated in many mammalian CNS neurons by the glutamate analog NMDA is inhibited at hyperpolarized potentials by extracellular magnesium. Whole-cell recordings from hippocampal neurons in culture were used to determine the voltage dependence of the NMDA conductance in the presence of extracellular magnesium concentrations from 1 microM to 10 mM. The conductance-voltage data are well fitted by a gating function derived from rate constants determined in an earlier study of the kinetic behavior of single channels activated by NMDA. The results are consistent with the assumption that magnesium inhibits current through the NMDA-activated channel by directly blocking the ion pore. In addition, another voltage-dependent blocking or flicker-producing mechanism has to be invoked to account for the behavior of the conductance at both the single-channel and whole-cell level, especially at low concentrations of extracellular magnesium.