Premature contractions of the bladder are suppressed by interactions between TRPV4 and SK3 channels in murine detrusor PDGFRα+ cells
Premature contractions of the bladder are suppressed by interactions between TRPV4 and SK3 channels in murine detrusor PDGFRα+ cells
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DOI：
10.1038/s41598-017-12561-7
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发表时间：
2017-09-25
影响因子：
4.6
通讯作者：
Koh, Sang Don
中科院分区：
文献类型：
--
作者：
Lee, Haeyeong;Koh, Byoung H.;Koh, Sang Don
在充盈过程中，膀胱体积急剧增加，压力变化不大。这是通过抑制膀胱壁逼尿肌的收缩来实现的。在充盈过程中负责调节逼尿肌收缩的机制知之甚少。在这里，我们描述了一种新的途径，以稳定逼尿肌兴奋性，涉及血小板衍生生长因子受体阳性（PDGFR α（+））间质细胞。PDGFR α（+）细胞表达小电导Ca（2+）激活的K+（SK）和TRPV 4通道。我们发现，在膀胱充盈期间，通过机械敏感性TRPV 4通道的Ca 2+进入稳定逼尿肌兴奋性。GSK 1016790 A（GSK）是TRPV 4通道激动剂，激活了与SK通道激活偶联的非选择性阳离子电导。GSK诱导PDGFR α（+）细胞超极化，并减少逼尿肌收缩。收缩也受到抑制的SK通道的激活。TRPV 4或SK通道阻断剂抑制GSK激活的电流，并增加逼尿肌收缩。TRPV 4和SK通道阻滞剂也增加了完整膀胱在充盈过程中的收缩。在充盈期间，Trpv 4（-/-）小鼠的膀胱中也发生了类似的收缩增强。SK通道激活剂（SKA-31）减少了充盈期间的收缩，并挽救了Trpv 4（-/-）膀胱的过度活动。我们的研究结果证明了通过TRPV 4通道的Ca 2+内流如何激活PDGFR α（+）细胞中的SK通道并防止充盈期间的膀胱过度活动。
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-a positive (PDGFR alpha(+)) interstitial cells. PDGFR alpha(+) cells express small conductance Ca(2+)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 PDGFR alpha(+) 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 PDGFR alpha(+) cells and prevent bladder overactivity during filling.