TRPV4 activity regulates nuclear Ca2+ and transcriptional functions of β-catenin in a renal epithelial cell model

TRPV4 is a nonselective cationic channel responsive to several physical and chemical stimuli. Defects in TRPV4 channel function result in human diseases, such as skeletal dysplasias, arthropathies, and peripheral neuropathies. Nonetheless, little is known about the role of TRPV4 in other cellular functions, such as nuclear Ca2+ homeostasis or Ca2+-regulated transcription. Here, we confirmed the presence of the full-length TRPV4 channel in the nuclei of nonpolarized Madin-Darby canine kidney cells. Confocal Ca2+ imaging showed that activation of the channel increases cytoplasmic and nuclear Ca2+ leading to translocation of TRPV4 out of the nucleus together with beta-catenin, a transcriptional regulator in the Wnt signaling pathway fundamental in embryogenesis, organogenesis, and cellular homeostasis. TRPV4 inhibits beta-catenin transcriptional activity through a direct interaction dependent upon channel activity. This interaction also occurs in undifferentiated osteoblastoma and neuroblastoma cell models. Our results suggest a mechanism in which TRPV4 may regulate differentiation in several cellular contexts.

Automated summary

TRPV4 channel functions in the nucleus, inhibiting the transcriptional activity of beta-catenin through a direct interaction, and may regulate differentiation in various cellular contexts.