TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells
TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells
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DOI：
10.1073/pnas.0803970105
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发表时间：
2008-08-26
影响因子：
11.1
通讯作者：
Valverde, Miguel A.
中科院分区：
文献类型：
--
作者：
Lorenzo, Ivan M.;Liedtke, Wolfgang;Valverde, Miguel A.
气道中纤毛黏液清除率是纤毛搏动频率（CBF）的函数，而这反过来又随着细胞内钙的增加而增加。TRPV4阳离子通道介导Ca2+内流响应机械和渗透刺激纤毛上皮。通过使用TRPV4缺陷小鼠，我们现在发现TRPV4参与气道对生理相关的物理和化学刺激的反应。免疫荧光法证实TRPV4阳性/阳性小鼠纤毛TRPV4在气管上皮细胞中的表达。TRPV4（-/-）小鼠纤毛气管细胞对合成激活剂4 α -phorbol 12,13-didecanoate （4 α PDD）的反应没有增加细胞内Ca2+和CBF，对另一种TRPV4激活刺激的反应降低。尽管Ca2+信号减少，但在TRPV4（-/-）中，CBF对高粘度溶液的自动调节仍被保留。更有趣的是，TRPV4促进了atp诱导的CBF增加，提供了受体操作的Ca2+进入途径，而不是存储操作的Ca2+进入途径，因为前者机制在TRPV4（-/-）细胞中丢失。综上所述，这些结果表明TRPV4主要位于气管上皮细胞的纤毛中，并在将物理和化学刺激转导为调节CBF和纤毛黏液运输的Ca2+信号中发挥关键作用。此外，这些研究暗示TRPV4参与受体操作的Ca2+进入。
The rate of mucociliary clearance in the airways is a function of ciliary beat frequency (CBF), and this, in turn, is increased by increases in intracellular calcium. The TRPV4 cation channel mediates Ca2+ influx in response to mechanical and osmotic stimuli in ciliated epithelia. With the use of a TRPV4-deficient mouse, we now show that TRPV4 is involved in the airways' response to physiologically relevant physical and chemical stimuli. Ciliary TRPV4 expression in tracheal epithelial cells was confirmed with immunofluorescence in TRPV4(+/+) mice. Ciliated tracheal cells from TRPV4(-/-) mice showed no increases in intracellular Ca2+ and CBF in response to the synthetic activator 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD) and reduced responses to mild temperature, another TRPV4-activating stimulus. Autoregulation of CBF in response to high viscosity solutions is preserved in TRPV4(-/-) despite a reduced Ca2+ signal. More interestingly, TRPV4 contributed to an ATP-induced increase in CBF, providing a pathway for receptor-operated Ca2+ entry but not store-operated Ca2+ entry as the former mechanism is lost in TRPV4(-/-) cells. Collectively, these results suggest that TRPV4 is predominantly located in the cilia of tracheal epithelial cells and plays a key role in the transduction of physical and chemical stimuli into a Ca2+ signal that regulates CBF and mucociliary transport. Moreover, these studies implicate the participation of TRPV4 in receptor-operated Ca2+ entry.