Swelling-activated Ca2+ entry via TRPV4 channel is defective in cystic fibrosis airway epithelia
Swelling-activated Ca2+ entry via TRPV4 channel is defective in cystic fibrosis airway epithelia
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DOI：
10.1074/jbc.m409708200
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发表时间：
2004-12-24
影响因子：
4.8
通讯作者：
Valverde, MA
中科院分区：
文献类型：
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作者：
Arniges, M;Vázquez, E;Valverde, MA
脊椎动物瞬时受体电位阳离子通道TRPV4已被提出作为渗透和机械传感器通道。使用敲除动物模型的研究进一步强调了TRPV4通道在维持内部渗透平衡和机械感觉中的相关性。然而，在细胞水平上，仍然有一个重要的问题需要回答：TRPV4通道是否在那些经历Ca2+依赖性调节体积减少（RVD）反应的细胞中产生Ca2+信号？人气道上皮的RVD需要Ca2+信号的产生来激活Ca2+依赖的K+通道。囊性纤维化（CF）是一种由囊性纤维化跨膜传导调节通道突变引起的疾病。我们之前已经表明，CF上皮中有缺陷的RVD与Ca2+依赖性K+通道缺乏肿胀依赖性激活有关。在本研究中，我们展示了TRPV4在正常人气道上皮中的表达，正如TRPV4反义实验所证明的那样，它在低渗应激后作为Ca2+进入途径触发RVD反应。然而，CF气道上皮细胞肿胀不能触发Ca2+通过TRPV4通道进入，尽管该通道对特定的合成激活剂4α -phorbol 12,13-didecanoate的反应得以维持。此外，4 α -phorbol 12,13-didecanoate治疗CF气道上皮RVD恢复。综上所述，这些结果表明CF气道上皮RVD缺陷可能是由trpv4介导的Ca2+信号缺失和随后Ca2+依赖性K+通道的激活引起的。
The vertebrate transient receptor potential cationic channel TRPV4 has been proposed as an osmo- and mechanosensor channel. Studies using knock-out animal models have further emphasized the relevance of the TRPV4 channel in the maintenance of the internal osmotic equilibrium and mechanosensation. However, at the cellular level, there is still one important question to answer: does the TRPV4 channel generate the Ca2+ signal in those cells undergoing a Ca2+-dependent regulatory volume decrease (RVD) response? RVD in human airway epithelia requires the generation of a Ca2+ signal to activate Ca2+-dependent K+ channels. The RVD response is lost in airway epithelia affected with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator channel. We have previously shown that the defective RVD in CF epithelia is linked to the lack of swelling-dependent activation of Ca2+-dependent K+ channels. In the present study, we show the expression of TRPV4 in normal human airway epithelia, where it functions as the Ca2+ entry pathway that triggers the RVD response after hypotonic stress, as demonstrated by TRPV4 antisense experiments. However, cell swelling failed to trigger Ca2+ entry via TRPV4 channels in CF airway epithelia, although the channel's response to a specific synthetic activator, 4alpha-phorbol 12,13-didecanoate, was maintained. Furthermore, RVD was recovered in CF airway epithelia treated with 4alpha-phorbol 12,13-didecanoate. Together, these results suggest that defective RVD in CF airway epithelia might be caused by the absence of a TRPV4-mediated Ca2+ signal and the subsequent activation of Ca2+-dependent K+ channels.