Voltage-dependent inhibition of RCK1 K+ channels by phenol, p-cresol, and benzyl alcohol.
Phenol has various medical applications but can cause convulsions and cardiac arrhythmia suggestive of K+ channel block. We examined phenol inhibition of the delayed-rectifier RCK1 (Kv1.1) K+ channel cloned from rat brain and expressed in Xenopus laevis oocytes. Phenol (2.5 mM) caused a 43 +/- 5 mV depolarizing shift in the RCK1 half-activation voltage (Vg) but only a 10 +/- 3% decrease in the peak conductance at 80 mV. The 10-90% rise time was slightly increased, but this was not simply the result of the activation shift. By contrast, deactivation kinetics at -40 mV were greatly accelerated. The importance of the phenolic hydroxyl group was assessed by comparing the effects of p-cresol (a phenol) and its structural isomer benzyl alcohol (an aryl alcohol). p-Cresol (1.5 mM) produced a 53 +/- 2 mV depolarizing shift in Vg, but benzyl alcohol was much less effective--20 mM caused a depolarizing shift of only 23 +/- 1 mV. Both isomers also accelerated channel deactivation. Phenol and p-cresol are better hydrogen bond donors than acceptors, whereas benzyl alcohol is a better acceptor than donor. A hydrogen bond between the phenolic hydroxyl and a presently unknown acceptor group may therefore underlie some aspects of K+ channel inhibition. Depolarizing shifts in Vg and accelerated tail kinetics are consistent with 1) preferential phenol binding to resting channels, causing the shift in Vg, and 2) a conducting phenol-bound open state with faster deactivation kinetics than the unbound open state.
Elliott
A A
AA
Department of Anatomy and Physiology, University of Dundee, Scotland.
Elliott
J R
JR
D000818:Animals; D019905:Benzyl Alcohol; D001592:Benzyl Alcohols / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D003001:Cloning, Molecular; D003408:Cresols / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D008564:Membrane Potentials; D009865:Oocytes; D019800:Phenol; D010636:Phenols / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D014982:Xenopus laevis
D001592:Benzyl Alcohols; D003408:Cresols; D010636:Phenols; D015221:Potassium Channels; C032538:4-cresol; D019800:Phenol; D019905:Benzyl Alcohol