Slow voltage-dependent changes in channel open-state probability underlie hysteresis of NMDA responses in Mg(2+)-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 Mg(2+)-free solutions we discovered that N-methyl-D-aspartate (NMDA) channels in excised patches reversibly shifted their open-state probability (Po) in a voltage-dependent way, exhibiting approximately 3- to 4-fold greater Po at positive potentials than at rest. Changes in Po were mainly attributable to shifts in frequency of channel opening. Po changed remarkably slowly (2-15 min), explaining the hysteresis of whole-cell current-voltage curves obtained in nonequilibrium conditions. The slow increase in Po 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.
Nowak
L M
LM
Department of Pharmacology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
Wright
J M
JM
D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials; D051379:Mice; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology*; D011336:Probability; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D007473:Ion Channels; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D008274:Magnesium; D004229:Dithiothreitol