title: Four-mode gating model of fast inactivation of sodium channel Nav1.2a.
abstract: Basic principles of the gating mechanisms of neuronal sodium channels, especially the fast inactivation process, were revealed by a quantitative analysis of the effects of the chemically irreversible modifying agent chloramine T. The compound is known to enhance the open probability of sodium channels by interfering with the inactivation process. The key for the deduction of structure-function relationships was obtained from the analysis of single-channel patch-clamp data, especially the finding that chloramine T-induced modification of inactivation occurred in four steps. These steps were termed modes 1-4 (four-mode gating model), and their temporal sequence was always the same. The kinetic analysis of single-channel traces with an improved two-dimensional dwell-time fit revealed the possible mechanism related to each mode. Similarities to the kinetics of the sodium channel mutant F1489Q led to the assignment of modes 1 and 2 to transient defects in the locking of the inactivation particle (hinged lid). In the third mode, the hinged lid was unable to lock permanently. Finally, in mode 4, the apparent single-channel current was reduced, which could be explained by fast gating, presumably related to the selectivity filter.
authors.affiliation: Department of Physiology, University of Kiel, Olshausenstrasse 40, 24098, Kiel, Germany. t.huth@physiologie.uni-kiel.de
authors.forename: Tobias
authors.initials: T
authors.lastname: Huth
authors.forename: Johann
authors.initials: J
authors.lastname: Schmidtmayer
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Ulf-Peter
authors.initials: UP
authors.lastname: Hansen
mesh_terms: D000465:Algorithms; D002460:Cell Line; D002700:Chloramines / Q000494:pharmacology; D003198:Computer Simulation; D004594:Electrophysiology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology*; D008390:Markov Chains; D008954:Models, Biological; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000502:physiology*; D016011:Normal Distribution; D018408:Patch-Clamp Techniques; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology*; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D002700:Chloramines; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568251:SCN2A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014105:Tosyl Compounds; C016300:chloramine-T