Abstract
The large-conductance calcium-activated potassium channel (BKCa channel) plays critical roles in smooth muscle relaxation. In urinary bladder smooth muscle, BKCa channel activity underlies the maintenance of the resting membrane potential and repolarization of the spontaneous action potential triggering the phasic contraction. To identify novel BKCa channel activators, we screened a library of natural compounds using a cell-based fluorescence assay and a hyperactive mutant BKCa channel (Lee et al., 2013). From 794 natural compounds, kurarinone, a flavanone from Sophora flavescens, strongly potentiated BKCa channels. When treated from the extracellular side, this compound progressively shifted the conductance-voltage relationship of BKCa channels to more negative voltages and increased the maximum conductance in a dose-dependent manner. Whereas kurarinone strongly potentiated the homomeric BKCa channel composed of only the α subunit, its effects were much smaller on heteromeric channels coassembled with auxiliary β subunits. Although the activation kinetics was not altered significantly, the deactivation of BKCa channels was dramatically slowed by kurarinone treatment. At the single-channel level, kurarinone increased the open probability of the BKCa channel without affecting its single-channel conductance. Kurarinone potently relaxed acetylcholine-induced contraction of rat bladder smooth muscle and thus decreased the micturition frequency of rats with overactive bladder symptoms. These results indicate that kurarinone can directly potentiate BKCa channels and demonstrate the therapeutic potentials of kurarinone and its derivatives for developing antioveractive bladder medications and supplements.
Footnotes
- Received December 14, 2015.
- Accepted May 31, 2016.
↵1 Current affiliation: Department of Anesthesiology, Weill Cornell Medical College, New York, NY.
This work was supported by grants from the Korea Healthcare Technology Research and Development Project [Grant HI13C1412], Ministry for Health and Welfare, the National Leading Research Laboratories [Grant 2011-0028665], and the Science Research Center of Excellence Program [Grant 2007-0056157] of the Ministry of Science, ICT & Future Planning/National Research Foundation of Korea to C.S.P.
↵This article has supplemental material available at molpharm.aspetjournals.com.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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