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 (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 inVg 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.
Footnotes
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Send reprint requests to: Dr. J.R. Elliott, Department of Anatomy and Physiology, University of Dundee, Dundee DD1 4HN, United Kingdom. E-mail: j.r.elliott{at}dundee.ac.uk
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This work was supported by the Wellcome Trust and the University of Dundee.
- Abbreviations:
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- Vg
- half-activation voltage
- ΔVg
- shift inVg
- kg
- mid-point slope of the activation curve
- gK
- chord conductance
- I-V
- current-voltage
- Received August 6, 1996.
- Accepted December 3, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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