title: Effect of phenytoin on sodium conductances in rat hippocampal CA1 pyramidal neurons.
abstract: The antiepileptic drug phenytoin (PHT) is thought to reduce the excitability of neural tissue by stabilizing sodium channels (NaV) in inactivated states. It has been suggested the fast-inactivated state (IF) is the main target, although slow inactivation (IS) has also been implicated. Other studies on local anesthetics with similar effects on sodium channels have implicated the NaVvoltage sensor interactions. In this study, we reexamined the effect of PHT in both equilibrium and dynamic transitions between fast and slower forms of inactivation in rat hippocampal CA1 pyramidal neurons. The effects of PHT were observed on fast and slow inactivation processes, as well as on another identified "intermediate" inactivation process. The effect of enzymatic removal of IFwas also studied, as well as effects on the residual persistent sodium current (INaP). A computational model based on a gating charge interaction was derived that reproduced a range of PHT effects on NaVequilibrium and state transitions. No effect of PHT on IFwas observed; rather, PHT appeared to facilitate the occupancy of other closed states, either through enhancement of slow inactivation or through formation of analogous drug-bound states. The overall significance of these observations is that our data are inconsistent with the commonly held view that the archetypal NaVchannel inhibitor PHT stabilizes fast inactivation states, and we demonstrate that conventional slow activation "IS" and the more recently identified intermediate-duration inactivation process "II" are the primary functional targets of PHT. In addition, we show that the traditional explanatory frameworks based on the "modulated receptor hypothesis" can be substituted by simple, physiologically plausible interactions with voltage sensors. Additionally, INaPwas not preferentially inhibited compared with peak INaat short latencies (50 ms) by PHT.
authors.affiliation: Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Elisa L
authors.initials: EL
authors.lastname: Hill-Yardin
authors.affiliation: Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; and.
authors.forename: Terence
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andris
authors.initials: A
authors.lastname: Serelis
authors.affiliation: Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; and frenchc@unimelb.edu.au.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: French
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008959:Models, Neurological; D018408:Patch-Clamp Techniques; D010672:Phenytoin / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D046509:Tissue Culture Techniques; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D015222:Sodium Channels; D061567:Voltage-Gated Sodium Channel Blockers; D010672:Phenytoin; D012964:Sodium
keywords: CA1; hippocampus; phenytoin; rat