Abstract
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 Ca2+-activated K+ (SK) and TRPV4 channels. We found that Ca2+ 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 Ca2+ influx through TRPV4 channels can activate SK channels in PDGFRα+ cells and prevent bladder overactivity during filling.
Highlights
Overactive bladder is a clinical syndrome accounting for over $12 billion in health care costs in the USA annually[1]
We investigated the expression of Trp genes in PDGFRα+ cells
We focused our investigations on the functional role of TRPV4 channels in PDGFRα+ cells since TRPC1 and TRPM5 channels are less permeable to divalent cations
Summary
Overactive bladder is a clinical syndrome accounting for over $12 billion in health care costs in the USA annually[1]. PDGFRα+ cells have been identified in human and guinea pig detrusor muscles[4] These cells are closely associated with varicose nerve processes in detrusor muscles (muscularis propria) suggesting that PDGFRα+ cells may be innervated and participate in purinergic regulation of bladder contraction[5,6,7]. Stabilization of bladder excitability by SK channels appears to be due to the prominent expression of these channels in PDGFRα+ cells rather than in SMCs. SK channels are activated by increased intracellular Ca2+ 12,13. We tested the hypothesis that TRPV4 channels are expressed primarily by PDGFRα+ cells in detrusor muscles, and that Ca2+ entry via TRPV4 channels is linked to activation of SK channels. It is possible that enhanced Ca2+ influx via TRPV4 channels during bladder filling increases the open probability of SK channels to dampen the excitability of detrusor muscles. Our results show that SK channel activation is closely linked to TRPV4-mediated Ca2+-influx and may be enhanced by direct interactions between TRPV4 and SK3 channels in PDGFRα+ cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
