TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells

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Abstract
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 Ca 2+ 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 Ca 2+ and CBF in response to the synthetic activator 4α-phorbol 12,13-didecanoate (4αPDD) 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 Ca 2+ signal. More interestingly, TRPV4 contributed to an ATP-induced increase in CBF, providing a pathway for receptor-operated Ca 2+ entry but not store-operated Ca 2+ 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 Ca 2+ signal that regulates CBF and mucociliary transport. Moreover, these studies implicate the participation of TRPV4 in receptor-operated Ca 2+ entry.

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