The anti-epileptic drug phenytoin (PHT) is thought to reduce the excitability of neural tissue by stabilising sodium channels (NaV) in inactivated states (Rogawski and Loscher 2004). It has been suggested the fast inactivated state ("IF") is the main target (Kuo and Bean, 1994), though slow inactivation ("IS") has also been implicated (Quandt, 1988). Other studies on local anaesthetics with similar effects on sodium channels have implicated the NaV voltage sensor interactions (Muroi and Chanda, 2009). Here, we re-examine 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 on fast, slow and another identified "intermediate" inactivation processes were observed. The effect of enzymatic removal of fast inactivation was 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 NaV equilibrium and state transitions. No effect of PHT on IF was observed, rather phenytoin 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 Nav channel inhibitor phenytoin stabilises fast inactivation states, and we demonstrate that conventional slow inactivation "IS" as well as a more recently identified "intermediate" duration inactivation process I1 are the primary functional targets of phenytoin. Additionally, we show that the traditional explanatory frameworks based on the "modulated receptor hypothesis" (Hille 1976) can be substituted by simple, physiologically plausible interactions with voltage sensors. AdditionallyaP was not preferentially inhibited compared with peak INa at short latencies (50 ms) by PHT.
- Copyright © 2015, Journal of Neurophysiology