{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRPV4 is a polymodal, Ca²⁺‐permeable nonselective cation channel that is activated by a diverse array of physical and chemical stimuli. It functions as a temperature sensor in endothelial cells, where warming triggers Ca²⁺ influx and downstream signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Additionally, TRPV4 is activated by ligands such as phorbol derivatives, as well as by cell swelling, mechanical strain, and altered medium viscosity, thereby integrating osmotic and mechanical stimuli to rapidly modulate intracellular Ca²⁺ levels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "7"}]}, {"type": "t", "text": " In astrocytes, for example, a functional TRPV4 complex with aquaporin‐4 is essential for regulatory volume decrease, while in airway smooth muscle and epithelia, hypotonic challenges similarly trigger TRPV4‐mediated Ca²⁺ entry."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMolecular and genetic studies have revealed that the precise gating and ion permeation properties of TRPV4 depend on specific structural determinants—including aspartate residues in its pore region and lipid‐binding elements in its intracellular domains—and that its activity is modulated by intracellular Ca²⁺ (and calmodulin), phosphorylation by kinases, and binding of regulatory proteins. Notably, mutations in TRPV4 underlie a spectrum of human channelopathies ranging from skeletal dysplasias to forms of peripheral neuropathy and arthropathy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": " In sensory neurons and visceral afferents, TRPV4 is implicated in thermosensation and mechanosensation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", while distinct mutations associated with Charcot‐Marie‐Tooth disease type 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy have been linked to either gain‐ or loss‐of channel function, aberrant trafficking, or altered regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "21"}]}, {"type": "t", "text": " Moreover, modulation of TRPV4 by interactions with phosphoinositides and regulatory proteins such as PACSIN3 has emerged as a critical mechanism controlling channel activation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", and studies have demonstrated that disease‐associated mutations can disrupt these interactions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role as a sensor, TRPV4 orchestrates numerous physiological processes in multiple tissues. In the cardiovascular system, TRPV4‐mediated Ca²⁺ influx in endothelial cells under shear stress promotes vasodilation, modulates reactive oxygen species formation, and supports endothelial homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "30"}]}, {"type": "t", "text": " In epithelial tissues, TRPV4 participates in water homeostasis, barrier formation, and regulatory volume control by interacting with structural proteins and other ion channels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "34"}]}, {"type": "t", "text": " Recent work has extended the physiological relevance of TRPV4 to inflammatory processes and tumor angiogenesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": ", while its contribution to ocular outflow resistance and intraocular pressure renders it a promising target for glaucoma treatment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": " In addition, TRPV4 influences the responses of lung and brain tissues in injury and glioma models"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "40"}]}, {"type": "t", "text": ", and emerging evidence in sensory and skin cells further emphasizes its role in barrier maintenance and mechanotransduction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroyuki Watanabe, John B Davis, Darren Smart, et al. 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