Swelling-activated Ca2+ entry via TRPV4 channel is defective in cystic fibrosis airway epithelia

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.