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

• Published in: Molecular pharmacology Vol. 90; no. 2; p. 140
• Main Authors: Lee, Sojung, Chae, Mee Ree, Lee, Byoung-Cheol, Kim, Yong-Chul, Choi, Jae Sue, Lee, Sung Won, Cheong, Jae Hoon, Park, Chul-Seung
• Format: Journal Article
• Language: English
• Published: United States 01-08-2016
• Subjects: Acetylcholine - pharmacology; Animals; Calcium - metabolism; Cell Line; Flavonoids - chemistry; Flavonoids - pharmacology; Fluorescence; Humans; In Vitro Techniques; Intracellular Space - metabolism; Ion Channel Gating - drug effects; Kinetics; Large-Conductance Calcium-Activated Potassium Channels - metabolism; Male; Muscle Relaxation - drug effects; Protein Subunits - metabolism; Rats, Inbred SHR; Rats, Sprague-Dawley; Structure-Activity Relationship; Urinary Bladder - drug effects; Urinary Bladder - physiology; Urination - drug effects; Xenopus laevis
• ISSN: 1521-0111
• DOI: 10.1124/mol.115.102939

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.