Long-lasting modification of the N-methyl-D-aspartate receptor channel by a voltage-dependent sulfhydryl redox process.
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.
Tang
L H
LH
Department of Neurobiology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Aizenman
E
E
D000818:Animals; D002478:Cells, Cultured; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology*; D004229:Dithiothreitol / Q000494:pharmacology*; D004553:Electric Conductivity; D004594:Electrophysiology; D008564:Membrane Potentials; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010084:Oxidation-Reduction; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology
D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D004228:Dithionitrobenzoic Acid; D004229:Dithiothreitol