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Research ArticleArticle

A Novel Role of Uricosuric Agent Benzbromarone in BK Channel Activation and Reduction of Airway Smooth Muscle Contraction

Jian Gao, Hao Yin, Yanqun Dong, Xintong Wang, Yani Liu and KeWei Wang
Molecular Pharmacology April 2023, 103 (4) 241-254; DOI: https://doi.org/10.1124/molpharm.122.000638
Jian Gao
Department of Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China (J.G., X.W.); Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (H.Y., Y.D., Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.)
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Hao Yin
Department of Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China (J.G., X.W.); Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (H.Y., Y.D., Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.)
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Yanqun Dong
Department of Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China (J.G., X.W.); Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (H.Y., Y.D., Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.)
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Xintong Wang
Department of Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China (J.G., X.W.); Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (H.Y., Y.D., Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.)
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Yani Liu
Department of Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China (J.G., X.W.); Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (H.Y., Y.D., Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.)
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KeWei Wang
Department of Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China (J.G., X.W.); Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao, China (H.Y., Y.D., Y.L., K.W.); and Institute of Innovative Drugs, Qingdao University, Qingdao, China (Y.L., K.W.)
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Abstract

The uricosuric drug benzbromarone, widely used for treatment of gout, hyperpolarizes the membrane potential of airway smooth muscle cells, but how it works remains unknown. Here we show a novel role of benzbromarone in activation of large conductance calcium-activated K+ channels. Benzbromarone results in dose-dependent activation of macroscopic big potassium (BK) currents about 1.7- to 14.5-fold with an EC50 of 111 μM and shifts the voltage-dependent channel activation to a more hyperpolarizing direction about 10 to 54 mV in whole-cell patch clamp recordings. In single-channel recordings, benzbromarone decreases single BKα channel closed dwell time and increases the channel open probability. Coexpressing β1 subunit also enhances BK activation by benzbromarone with an EC50 of 67 μM and a leftward shift of conductance-voltage (G-V) curve about 44 to 138 mV. Site-directed mutagenesis reveals that a motif of three amino acids 329RKK331 in the cytoplasmic linker between S6 and C-terminal regulator of potassium conductance (RCK) gating ring mediates the pharmacological activation of BK channels by benzbromarone. Further ex vivo assay shows that benzbromarone causes reduction of tracheal strip contraction. Taken together, our findings demonstrate that uricosuric benzbromarone activates BK channels through molecular mechanism of action involving the channel RKK motif of S6-RCK linker. Pharmacological activation of BK channel by benzbromarone causes reduction of tracheal strip contraction, holding a repurposing potential for asthma and pulmonary arterial hypertension or BK channelopathies.

SIGNIFICANCE STATEMENT We describe a novel role of uricosuric agent benzbromarone in big potassium (BK) channel activation and relaxation of airway smooth muscle contraction. In this study, we find that benzbromarone is an activator of the large-conductance Ca2+- and voltage-activated K+ channel (BK channel), which serves numerous cellular functions, including control of smooth muscle contraction. Pharmacological activation of BK channel by the FDA-approved drug benzbromarone may hold repurposing potential for treatment of asthma and pulmonary arterial hypertension or BK channelopathies.

Footnotes

    • Received October 12, 2022.
    • Accepted December 19, 2022.
  • This work was supported by research grants awarded to K.W. from the National Natural Sciences Foundation of China [Grant 81573410], the Ministry of Science and Technology of China [Grant 2018ZX09711001-004-006], the Natural Sciences Foundation of Shandong Province [Grant ZR2015QL008], and the Science and Technology Program of Guangdong [Grant 2018B030334001].

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • ↵1Current affiliation: Washington University, St. Louis, Missouri.

  • dx.doi.org/10.1124/molpharm.122.000638.

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

  • Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (4)
Molecular Pharmacology
Vol. 103, Issue 4
1 Apr 2023
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Research ArticleArticle

Benzbromarone Relaxes Airway Smooth Muscle via BK Activation

Jian Gao, Hao Yin, Yanqun Dong, Xintong Wang, Yani Liu and KeWei Wang
Molecular Pharmacology April 1, 2023, 103 (4) 241-254; DOI: https://doi.org/10.1124/molpharm.122.000638

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Research ArticleArticle

Benzbromarone Relaxes Airway Smooth Muscle via BK Activation

Jian Gao, Hao Yin, Yanqun Dong, Xintong Wang, Yani Liu and KeWei Wang
Molecular Pharmacology April 1, 2023, 103 (4) 241-254; DOI: https://doi.org/10.1124/molpharm.122.000638
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