TRPV4 channel is involved in the coupling of fluid viscosity changes to epithelial ciliary activity

Abstract

Autoregulation of the ciliary beat frequency (CBF) has been proposed as the mechanism used by epithelial ciliated cells to maintain the CBF and prevent the collapse of mucociliary transport under conditions of varying mucus viscosity. Despite the relevance of this regulatory response to the pathophysiology of airways and reproductive tract, the underlying cellular and molecular aspects remain unknown. Hamster oviductal ciliated cells express the transient receptor potential vanilloid 4 (TRPV4) channel, which is activated by increased viscous load involving a phospholipase A2–dependent pathway. TRPV4-transfected HeLa cells also increased their cationic currents in response to high viscous load. This mechanical activation is prevented in native ciliated cells loaded with a TRPV4 antibody. Application of the TRPV4 synthetic ligand 4α-phorbol 12,13-didecanoate increased cationic currents, intracellular Ca2+, and the CBF in the absence of a viscous load. Therefore, TRPV4 emerges as a candidate to participate in the coupling of fluid viscosity changes to the generation of the Ca2+ signal required for the autoregulation of CBF.

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

“…Therefore, Ca 2ϩ entry pathways designed to modulate CBF should be localized close to the base of the cilia within the apical membrane of the cell. Previously, TRPV4 has been principally localized at the base of the cilia of hamster oviduct cells (21), and its activation by the synthetic agonist 4␣PDD increased the CBF in these cells (22). In the present study, we show that TRPV4-specific immunoreactivity is restricted mostly to cilia of TRPV4 ϩ/ϩ tracheal epithelial cells, similar to hamster oviduct ciliated cells (21) and rat ciliated cholangiocytes (31), whereas the TRPV4 signal is absent in the cilia of epithelial cells obtained from TRPV4 Ϫ/Ϫ mice.…”

“…TRPV4 can be also sensitized by coapplication of different stimuli (18)(19)(20) or participation of different cell signaling pathways (21). TRPV4 messenger and protein have been identified in both native ciliated epithelial cells of oviducts (21)(22)(23) and cell lines derived from human ciliated airway cells (24). In these epithelial cells, the TRPV4 channel plays a key role in cell volume homeostasis, by activating Ca 2ϩ -dependent K ϩ channels (25,26) and in the regulation of CBF, by providing a Ca 2ϩ entry pathway in response to changes in fluid viscosity or tonicity (21,22).…”

“…TRPV4 messenger and protein have been identified in both native ciliated epithelial cells of oviducts (21-23) and cell lines derived from human ciliated airway cells (24). In these epithelial cells, the TRPV4 channel plays a key role in cell volume homeostasis, by activating Ca 2ϩ -dependent K ϩ channels (25,26) and in the regulation of CBF, by providing a Ca 2ϩ entry pathway in response to changes in fluid viscosity or tonicity (21,22). TRPV4 splice variants, some of which do not oligomerize and are retained intracellularly, have also been found in airway epithelial cell lines (27) (for detailed review on TRP splicing, see ref.…”

Tubal transport of gametes and embryos: a review of physiology and pathophysiology

“…Subsequent studies have demonstrated that other mediators, such as Platelet Activating Factor (PAF) may exert their stimulatory effect on CBF through an increase in PGE2 [40]. Changes in fluid viscosity has been linked to CBF with the teleologically explained aim of maintaining a constant level of CBF in the face of varying degrees of luminal fluid viscosity and it has been shown that the transient receptor potential vanilloid 4 (TRPV4) channel is involved in transmitting these extracellular signals to the intracellular ciliary apparatus [41].…”

Stimulus-specific Modulation of the Cation Channel TRPV4 by PACSIN 3

“…However, little is known about the mechanisms that regulate TRPV4 function in these different physiological settings, and it is unclear whether all known activation mechanisms are operating in every TRPV4-expressing cell. Heterologously expressed TRPV4 can be activated by a broad range of physical and chemical stimuli, including osmotic cell swelling (1,2,4,20,21), moderate heat (12,22), synthetic ligands stimuli as 4␣-phorbol 12,13-didecanoate (4␣-PDD) (13,23), mechanical force (14, 19, 24 -26), fluid viscosity (27), and endogenous ligands such as anandamide and arachidonic acid (AA)-derived epoxyeicosatrienoic acids (28 -30).…”