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

Area of Science:

• Molecular Biology
• Cell Biology
• Physiology

Background:

• Transient Receptor Potential Vanilloid 4 (TRPV4) channels are known to be activated by physical and chemical stimuli.
• Dysfunctional TRPV4 channels are implicated in various human diseases, including skeletal dysplasias, arthropathies, and peripheral neuropathies.
• The role of TRPV4 in nuclear calcium (Ca2+) homeostasis and Ca2+-regulated transcription remains largely unexplored.

Purpose of the Study:

• To investigate the presence and function of TRPV4 channels within the nucleus.
• To elucidate the role of nuclear TRPV4 in calcium signaling and transcriptional regulation.
• To determine the interaction between TRPV4 and β-catenin in nuclear processes.

Main Methods:

• Confirmation of full-length TRPV4 channel presence in the nuclei of Madin-Darby canine kidney cells.
• Confocal Ca2+ imaging to monitor cytoplasmic and nuclear Ca2+ levels upon TRPV4 activation.
• Co-immunoprecipitation and functional assays to assess TRPV4-β-catenin interaction and its effect on transcription.

Main Results:

• TRPV4 channels were confirmed to be present in the nuclei of kidney cells.
• Activation of nuclear TRPV4 increased both cytoplasmic and nuclear Ca2+ levels.
• TRPV4 translocated from the nucleus with β-catenin upon activation, inhibiting β-catenin's transcriptional activity via direct interaction.

Conclusions:

• TRPV4 channels are present and functional within the nucleus, regulating Ca2+ homeostasis.
• Nuclear TRPV4 directly interacts with β-catenin, modulating its transcriptional activity and potentially influencing Wnt signaling.
• These findings suggest a novel mechanism by which TRPV4 regulates cellular differentiation across various cell types.