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Functional coupling of TRPV4 channels and BK channels in regulating spontaneous contractions of the guinea pig urinary bladder

  • Muscle physiology
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Abstract

We investigated the role of TRPV4 channels (TRPV4) in regulating the contractility of detrusor smooth muscle (DSM) and muscularis mucosae (MM) of the urinary bladder. Distribution of TRPV4 in DSM and MM of guinea-pig bladders was examined by fluorescence immunohistochemistry. Changes in the contractility of DSM and MM bundles were measured using isometric tension recording. Intracellular Ca2+ dynamics were visualized by Cal-520 fluorescent Ca2+ imaging, while membrane potential changes were recorded using intracellular microelectrode technique. DSM and MM expressed TRPV4 immunoreactivity. GSK1016790A (GSK, 1 nM), a TRPV4 agonist, evoked a sustained contraction in both DSM and MM associated with a cessation of spontaneous phasic contractions in a manner sensitive to HC-067047 (10 μM), a TRPV4 antagonist. Iberiotoxin (100 nM) and paxilline (1 μM), large conductance Ca2+-activated K+ (BK) channel blockers restored the spontaneous contractions in GSK. The sustained contractions in DSM and MM were reduced by nifedipine (10 μM), a blocker of L-type voltage-dependent Ca2+ channels (LVDCCs) by about 40 % and by nominally Ca2+-free solution by some 90 %. GSK (1 nM) abolished spontaneous Ca2+ transients, increased basal Ca2+ levels and also prevented spontaneous action potential discharge associated with DSM membrane hyperpolarization. In conclusion, Ca2+ influx through TRPV4 appears to activate BK channels to suppress spontaneous contractions and thus a functional coupling of TRPV4 with BK channels may act as a self-limiting mechanism for bladder contractility during its storage phase. Despite the membrane hyperpolarization in GSK, Ca2+ entry mainly through TRPV4 develops the tonic contraction.

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Acknowledgments

The authors wish to thank Dr. Richard Lang (Monash University) for the critical reading of the manuscript. This study was supported by JSPS KAKENHI, Grant-in-Aid for Challenging Exploratory Research (no. 26670705) to H.H.

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Authors and Affiliations

  1. Department of Cell Physiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan

    Ayu Isogai, Ken Lee, Retsu Mitsui & Hikaru Hashitani

  2. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Ken Lee

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  1. Ayu Isogai
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  4. Hikaru Hashitani
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Correspondence to Hikaru Hashitani.

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The experimental protocols in the present study were approved by the Nagoya City University Medical School Experimental Animal Committee.

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Isogai, A., Lee, K., Mitsui, R. et al. Functional coupling of TRPV4 channels and BK channels in regulating spontaneous contractions of the guinea pig urinary bladder. Pflugers Arch - Eur J Physiol 468, 1573–1585 (2016). https://doi.org/10.1007/s00424-016-1863-0

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  • DOI: https://doi.org/10.1007/s00424-016-1863-0

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