Premature contractions of the bladder are suppressed by interactions between TRPV4 and SK3 channels in murine detrusor PDGFRα+ cells

• Published in: Scientific reports Vol. 7; no. 1; pp. 12245 - 14
• Main Authors: Lee, Haeyeong, Koh, Byoung H., Peri, Lauren E., Corrigan, Robert D., Lee, Hyun-Tai, George, Nikita E., Bhetwal, Bhupal P., Xie, Yeming, Perrino, Brian A., Chai, Toby C., Sanders, Kenton M., Koh, Sang Don
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.09.2017; Nature Publishing Group
• Subjects: 13/1; 13/51; 14/63; 631/443; 82/51; 82/80; 9/74; Animals; Bladder; Calcium channels; Calcium conductance; Calcium influx; Cells, Cultured; Contraction; Excitability; Humanities and Social Sciences; Hyperpolarization; Interstitial cells; Mice; multidisciplinary; Muscle Cells - chemistry; Muscle Cells - physiology; Muscle contraction; Platelet-derived growth factor; Potassium channels (calcium-gated); Potassium conductance; Receptor, Platelet-Derived Growth Factor alpha - analysis; Rodents; Science; Science (multidisciplinary); Small-Conductance Calcium-Activated Potassium Channels; TRPV Cation Channels; Urinary bladder; Urinary Bladder - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-12561-7

During filling, urinary bladder volume increases dramatically with little change in pressure. This is accomplished by suppressing contractions of the detrusor muscle that lines the bladder wall. Mechanisms responsible for regulating detrusor contraction during filling are poorly understood. Here we describe a novel pathway to stabilize detrusor excitability involving platelet-derived growth factor receptor-α positive (PDGFRα + ) interstitial cells. PDGFRα + cells express small conductance Ca 2+ -activated K + (SK) and TRPV4 channels. We found that Ca 2+ entry through mechanosensitive TRPV4 channels during bladder filling stabilizes detrusor excitability. GSK1016790A (GSK), a TRPV4 channel agonist, activated a non-selective cation conductance that coupled to activation of SK channels. GSK induced hyperpolarization of PDGFRα + cells and decreased detrusor contractions. Contractions were also inhibited by activation of SK channels. Blockers of TRPV4 or SK channels inhibited currents activated by GSK and increased detrusor contractions. TRPV4 and SK channel blockers also increased contractions of intact bladders during filling. Similar enhancement of contractions occurred in bladders of Trpv4 −/− mice during filling. An SK channel activator (SKA-31) decreased contractions during filling, and rescued the overactivity of Trpv4 −/− bladders. Our findings demonstrate how Ca 2+ influx through TRPV4 channels can activate SK channels in PDGFRα + cells and prevent bladder overactivity during filling.