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Research ArticleArticle

Urinary Bladder-Relaxant Effect of Kurarinone Depending on Potentiation of Large-Conductance Ca2+-Activated K+ Channels

Sojung Lee, Mee Ree Chae, Byoung-Cheol Lee, Yong-Chul Kim, Jae Sue Choi, Sung Won Lee, Jae Hoon Cheong and Chul-Seung Park
Molecular Pharmacology August 2016, 90 (2) 140-150; DOI: https://doi.org/10.1124/mol.115.102939
Sojung Lee
School of Life Sciences (S.L., B.-C.L., Y.-C.K., C.-S.P.) and National Leading Research Laboratory (S.L., B.-C.L., C.-S.P.), Gwangju Institute of Science and Technology, Gwangju; Department of Food Science and Nutrition, Pukyong National University, Busan (J.S.C.); Department of Pharmacology, Sahmyook University, Seoul (J.H.C.); and Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul (M.R.C., S.W.L.), Republic of Korea
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Mee Ree Chae
School of Life Sciences (S.L., B.-C.L., Y.-C.K., C.-S.P.) and National Leading Research Laboratory (S.L., B.-C.L., C.-S.P.), Gwangju Institute of Science and Technology, Gwangju; Department of Food Science and Nutrition, Pukyong National University, Busan (J.S.C.); Department of Pharmacology, Sahmyook University, Seoul (J.H.C.); and Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul (M.R.C., S.W.L.), Republic of Korea
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Byoung-Cheol Lee
School of Life Sciences (S.L., B.-C.L., Y.-C.K., C.-S.P.) and National Leading Research Laboratory (S.L., B.-C.L., C.-S.P.), Gwangju Institute of Science and Technology, Gwangju; Department of Food Science and Nutrition, Pukyong National University, Busan (J.S.C.); Department of Pharmacology, Sahmyook University, Seoul (J.H.C.); and Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul (M.R.C., S.W.L.), Republic of Korea
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Yong-Chul Kim
School of Life Sciences (S.L., B.-C.L., Y.-C.K., C.-S.P.) and National Leading Research Laboratory (S.L., B.-C.L., C.-S.P.), Gwangju Institute of Science and Technology, Gwangju; Department of Food Science and Nutrition, Pukyong National University, Busan (J.S.C.); Department of Pharmacology, Sahmyook University, Seoul (J.H.C.); and Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul (M.R.C., S.W.L.), Republic of Korea
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Jae Sue Choi
School of Life Sciences (S.L., B.-C.L., Y.-C.K., C.-S.P.) and National Leading Research Laboratory (S.L., B.-C.L., C.-S.P.), Gwangju Institute of Science and Technology, Gwangju; Department of Food Science and Nutrition, Pukyong National University, Busan (J.S.C.); Department of Pharmacology, Sahmyook University, Seoul (J.H.C.); and Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul (M.R.C., S.W.L.), Republic of Korea
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Sung Won Lee
School of Life Sciences (S.L., B.-C.L., Y.-C.K., C.-S.P.) and National Leading Research Laboratory (S.L., B.-C.L., C.-S.P.), Gwangju Institute of Science and Technology, Gwangju; Department of Food Science and Nutrition, Pukyong National University, Busan (J.S.C.); Department of Pharmacology, Sahmyook University, Seoul (J.H.C.); and Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul (M.R.C., S.W.L.), Republic of Korea
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Jae Hoon Cheong
School of Life Sciences (S.L., B.-C.L., Y.-C.K., C.-S.P.) and National Leading Research Laboratory (S.L., B.-C.L., C.-S.P.), Gwangju Institute of Science and Technology, Gwangju; Department of Food Science and Nutrition, Pukyong National University, Busan (J.S.C.); Department of Pharmacology, Sahmyook University, Seoul (J.H.C.); and Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul (M.R.C., S.W.L.), Republic of Korea
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Chul-Seung Park
School of Life Sciences (S.L., B.-C.L., Y.-C.K., C.-S.P.) and National Leading Research Laboratory (S.L., B.-C.L., C.-S.P.), Gwangju Institute of Science and Technology, Gwangju; Department of Food Science and Nutrition, Pukyong National University, Busan (J.S.C.); Department of Pharmacology, Sahmyook University, Seoul (J.H.C.); and Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul (M.R.C., S.W.L.), Republic of Korea
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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.

  • dx.doi.org/10.1124/mol.115.102939.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.com.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 90 (2)
Molecular Pharmacology
Vol. 90, Issue 2
1 Aug 2016
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Research ArticleArticle

Kurarinone Relaxes the Bladder by Potentiating BK Channels

Sojung Lee, Mee Ree Chae, Byoung-Cheol Lee, Yong-Chul Kim, Jae Sue Choi, Sung Won Lee, Jae Hoon Cheong and Chul-Seung Park
Molecular Pharmacology August 1, 2016, 90 (2) 140-150; DOI: https://doi.org/10.1124/mol.115.102939

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Research ArticleArticle

Kurarinone Relaxes the Bladder by Potentiating BK Channels

Sojung Lee, Mee Ree Chae, Byoung-Cheol Lee, Yong-Chul Kim, Jae Sue Choi, Sung Won Lee, Jae Hoon Cheong and Chul-Seung Park
Molecular Pharmacology August 1, 2016, 90 (2) 140-150; DOI: https://doi.org/10.1124/mol.115.102939
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