SLOW VOLTAGE-DEPENDENT CHANGES IN CHANNEL OPEN-STATE PROBABILITY UNDERLIE HYSTERESIS OF NMDA RESPONSES IN MG2+-FREE SOLUTIONS

Many single-channel studies rely on the assumption that the channels are functioning under steady-state conditions. In examining the basis for nonlinear whole-cell current-voltage curves in Mg2+-free solutions we discovered that N-methyl-D-aspartate (NMDA) channels in excised patches reversibly shifted their open-state probability (P(o)) in a voltage-dependent way, exhibiting approximately 3- to 4-fold greater P(o) at positive potentials than at rest. Changes in P(o) were mainly attributable to shifts in frequency of channel opening. P(o) changed remarkably slowly (2-15 min), explaining the hysteresis of whole-cell current-voltage curves obtained in nonequilibrium conditions. The slow increase in P(o) provides a mechanism by which NMDA channels can substantially increase Ca2+ influx in cells depolarized for prolonged periods of time and may play a role in excitotoxicity.