Long-lasting modification of the N-methyl-D-aspartate receptor channel by a voltage-dependent sulfhydryl redox...

Ionic currents through the N-methyl-D-aspartate (NMDA) receptor channel are modulated by sulfhydryl redox reagents. We report here a novel form of redox modulation that alters NMDA channel kinetics in a voltage-dependent manner. The effects of the thiol reductant dithiothreitol (DTT) and the oxidizing agent 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) on NMDA-activated whole-cell currents were examined at various transmembrane voltages in cultured rat cortical neurons. DTT produced a similar level of potentiation of NMDA-induced currents at both -60 mV and +30 mV. However, the reversal of this potentiation by a sulfhydryl-oxidizing agent was dependent on the holding potential, because DTNB decreased the DTT-potentiated NMDA responses more effectively at negative voltages. Interestingly, the NMDA peak current-voltage relationship became substantially outwardly rectifying when sequential DTT/DTNB treatments took place at a positive holding potential, but not under any other circumstances. Single-channel recordings from outside-out patches revealed that this phenomenon was likely produced by a significant and long-lasting 2.3-fold prolongation of the mean open time of NMDA channels at a positive holding potential. Thus, a voltage-dependent chemical alteration in NMDA receptor structure modified the kinetic properties of the associated ion channel.