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1 Division of Cellular and Molecular Physiology, Department of Medical Physiology, University of Copenhagen, DK-2200 Copenhagen N; and 2 NeuroSearch A/S, DK-2750 Ballerup, Denmark
Human cloned KCNQ4 channels were stably
expressed in HEK-293 cells and characterized with respect to function
and pharmacology. Patch-clamp measurements showed that the KCNQ4
channels conducted slowly activating currents at potentials more
positive than 
60 mV. From the Boltzmann function fitted to the
activation curve, a half-activation potential of 32 mV and an
equivalent gating charge of 1.4 elementary charges was determined. The
instantaneous current-voltage relationship revealed strong inward
rectification. The KCNQ4 channels were blocked in a voltage-independent
manner by the memory-enhancing M current blockers XE-991 and
linopirdine with IC50 values of 5.5 and 14 µM,
respectively. The antiarrhythmic KCNQ1 channel blocker bepridil
inhibited KCNQ4 with an IC50 value of 9.4 µM, whereas
clofilium was without significant effect at 100 µM. The
KCNQ4-expressing cells exhibited average resting membrane potentials of
56 mV in contrast to 12 mV recorded in the nontransfected cells. In
conclusion, the activation and pharmacology of KCNQ4 channels resemble
those of M currents, and it is likely that the function of the KCNQ4
channel is to regulate the subthreshold electrical activity of
excitable cells.
XE-991; linopirdine; bepridil; M current
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