The amino-terminal domain of TRPV4 channel is involved in its trafficking to the nucleus.

Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is a sensor for multiple physical and chemical stimuli of ubiquitous expression that participates in various functions either in differentiated tissues or during differentiation. We recently demonstrated the nuclear localization of the full-length TRPV4 in the renal epithelial cells MDCK and its interaction with the transcriptional regulator β-catenin. Here, we describe the presence of a functional nuclear localization signals (NLS) in the N-terminal domain of TRPV4. Simultaneous substitution R404Q, K405Q, and K407Q, produces a channel that fail to reach the nucleus, while K177Q, K178Q, and R179Q mutant channel reaches the nucleus but does not arrive to the plasma membrane (PM). Similar result was observed with the S824D phosphomimetic mutant and the K407E mutation associated with skeletal dysplasia. Structural analysis of these mutants showed important remodeling in their C-terminal domains. Our observations suggest that nucleus-PM trafficking of TRPV4 is important for its cellular functions and may help to explain some deleterious effect of mutations causing TRPV4 channelopathies.