LONG-LASTING MODIFICATION OF THE N-METHYL-D-ASPARTATE RECEPTOR-CHANNEL BY A VOLTAGE-DEPENDENT SULFHYDRYL REDOX PROCESS

Ionic currents through the NS-methyl-D-aspartate (NMDA) receptor chann el are modulated by sulfhydryl redox reagents. We report here a novel form of redox modulation that alters NMDA channel kinetics in a voltag e-dependent manner. The effects of the thiol reductant dithiothreitol (DTT) and the oxidizing agent 5,5'-dithio-bis(2-nitrobenzoic acid) (DT NB) on NMDA-activated whole-cell currents were examined at various tra nsmembrane voltages in cultured rat cortical neurons. DTT produced a s imilar level of potentiation of NMDA-induced currents at both -60 mV a nd +30 mV. However, the reversal of this potentiation by a sulfhydryl- oxidizing agent was dependent on the holding potential, because DTNB d ecreased the DTT-potentiated NMDA responses more effectively at negati ve voltages. Interestingly, the NMDA peak current-voltage relationship became substantially outwardly rectifying when sequential DTT/DTNB tr eatments took place at a positive holding potential, but not under any other circumstances. Single-channel recordings from outside-out patch es revealed that this phenomenon was likely produced by a significant and long-lasting 2.3-fold prolongation of the mean open time of NMDA c hannels at a positive holding potential. Thus, a voltage-dependent che mical alteration in NMDA receptor structure modified the kinetic prope rties of the associated ion channel.