1.A.4.2.5
Vanilloid receptor-related, osmotically activated channel, VR-OAC (also called TRPV4, VRL2, VROAC and Trp12); required for bladder voiding in mice (Gevaert et al., 2007). Regulated by Pacsin3 via its SH3 domain which affects its subcellular localization and inhibits its activity in a stimulus-specific fashion (D'hoedt et al., 2008). Responsible for autosomal dominant brachyolmia (Rock et al., 2008). Multiple gating mechanisms have been demonstrated for TRPV4 (Loukin et al., 2010). TRPV4 Ca²⁺ signalling regulates endothelial vascular function (Sonkusare et al., 2012) and adipose oxidative metabolism, inflammation and energy homeostasis (Ye et al. 2012).  H₂O₂ induces Ca²⁺ influx into microvascular endothelial cells via TrpV4 (Suresh et al. 2015). TrpV4 orthologs are volume-sensors, rather than osmo-sensors (Toft-Bertelsen et al. 2017) that mediate fluid secretion by the ciliary body. They are important for vertebrate vision by providing nutritive support to the cornea and lens, and by maintaining intraocular pressure (Jo et al. 2016). Interacts with the A-kinase anchor protein 5 (AKAP5 or AKAP79 of 427 aas; TC# 8.A.28.1.6; P24588) (Mack and Fischer 2017). Mutations in TRPV4 are associated with accelerated chondrogenic differentiation of dental pulp stem cells (Nonaka et al. 2019). The homolog in Cynops pyrrhogaster (85% identical) is inhibited by RN1734 and may play a role in the sperm acrosome reaction (Kon et al. 2019). TRPV4 antagonism attenuates aortic inflammation and remodeling via decreased smooth muscle cell activation and neutrophil transendothelial migration (Shannon et al. 2020). It forms a tight complex with CD98hc (TC# 8.A.9.2.2) and beta1 integrin (TC# 9.B.87.1.8) in focal adhesions where mechanochemical conversion takes place. CD98hc knock down inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming the mechanospecificity of this signaling response. Molecular analysis revealed that forces applied to beta1 integrin must be transmitted from its cytoplasmic C-terminus via the CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 in order to produce ultra-rapid, force-induced, channel activation within the focal adhesion (Potla et al. 2020). TRPV4 mutations, resulting in severe gain of function, cause mixed neuropathy and skeletal phenotypes in humans (Taga et al. 2022). Cell swelling, heat, and chemical agonists use distinct pathways for the activation of TRPV4 (Vriens et al. 2004). Human TRPV4 is involved in immune activation, and because of its diverse engagement in the neuronal and immune systems, it is a potential therapeutic target for several immune-related disorders (Acharya et al. 2022). It is one of the major non-selective cation channel proteins that plays a crucial role in sensing biotic and abiotic stresses, such as pathogen infection, temperature, mechanical pressure and osmotic pressure changes by regulating Ca²⁺ homeostasis (He et al. 2022). The structure of human TRPV4 in complex with GTPase RhoAhas been determined, providing a template for the design of future therapeutics for treatment of TRPV4-related diseases (Nadezhdin et al. 2023). AQP4-independent TRPV4 modulation of plasma membrane water permeability has been documented (Barile et al. 2023). The possibility to tune plasma membrane water permeability more finely through TRPV4 might represent a protective mechanism in cells constantly facing severe osmotic challenges to avoid the potential deleterious effects of the rapid cell swelling occurring via AQP channels (Barile et al. 2023).  Hydrophobic gating and bundle-crossing mechanisms co-exist and complement one and another in the human TRPV4 channel. In particular, a single hydrophilic mutation in the lower pore can increase pore hydration and reduce the ion permeation free energy barrier by about half without affecting the bundle crossing (Huang and Chen 2023).  TRPV4 plays a role in programmed cell death (Ma et al. 2024).  TRPV4 regulates collagen remodeling and could pave the way for new approaches to manage fibrotic lesions (Wang et al. 2024).  Inflammation-induced TRPV4 channels exacerbate blood-brain barrier dysfunction in multiple sclerosis (Hansen et al. 2024).  TRPV4 may promote hepatitis B virus (HBV) replication and capsid assembly via methylation modification (Zhang et al. 2024).  Calcium-activated potassium channels function as amplifiers of TRPV4-mediated pulmonary edema formation in male mice (Li et al. 2024). The human ortholog is 95% identical, and TRPV4 in human corneal epithelial cells, stabilizes the tear film, enhances natural cytokine communication, and suppresses detrimental immune responses (Harrell and Volarevic 2024),  A deficiency of endothelial TRPV4 cation channels ameliorates experimental abdominal aortic aneurysm (Qian et al. 2025).  Combined clinical, structural and cellular studies discriminated pathogenic and benign TRPV4 variants (Berth et al. 2025).