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The transient receptor potential vanilloid 4 (TRPV4) ion channel is a ubiquitously expressed Ca 2+ -permeable ion channel that controls intracellular calcium ([Ca 2+ ] i ) homeostasis in various types of cells. The physiological roles for TRPV4 are tissue specific and the mechanisms behind this specificity remain mostly unclarified. It is noteworthy that mutations in the TRPV4 channel have been associated to a broad spectrum of congenital diseases, with most of these mutations mainly resulting in gain-of-function. Mutations have been identified in human patients showing a variety of phenotypes and symptoms, mostly related to skeletal and neuromuscular disorders. Since TRPV4 is so widely expressed throughout the body, it comes as no surprise that the literature is growing in evidence linking this protein to malfunction in systems other than the skeletal and neuromuscular. In this review, we summarize the expression patterns of TRPV4 in several tissues and highlight findings of recent studies that address critical structural and functional features of this channel, particularly focusing on its interactions and signaling pathways related to Ca 2+ entry. Moreover, we discuss the roles of TRPV4 mutations in some diseases and pinpoint some of the mechanisms underlying pathological states where TRPV4's malfunction is prominent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)