Voltage-Dependent Inhibition of RCK1 K⁺ Channels by Phenol, p-Cresol, and Benzyl Alcohol

Abstract

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 inXenopus laevis oocytes. Phenol (2.5 mm) caused a 43 ± 5 mV depolarizing shift in the RCK1 half-activation voltage (V_g) 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 V_g, 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 inV_g and accelerated tail kinetics are consistent with 1) preferential phenol binding to resting channels, causing the shift in V_g, and 2) a conducting phenol-bound open state with faster deactivation kinetics than the unbound open state.