25+ Years of TRPV4: From Discovery to Translational Horizons

Transient receptor potential vanilloid member 4 (TRPV4) is a calcium-permeable, nonselective cation channel first described in 2000. Polymodally-activated, also by osmotic, mechanical, thermal, actinic, and chemical stimuli, TRPV4 has emerged as a versatile molecular integrator across a remarkable diversity of cell lineages and vertebrate organ systems. Re orthology to invertebrate TRPV channels, TRPV4 rescued osmotic and mechanical sensing in ASH nociceptor neurons of C. elegans mutant for OSM-9 TRPV channels. This chapter surveys the arc of TRPV4 research from foundational cloning to translational medicine target. For that, TRPV4 expression, channel function, and (patho-)physiological roles as deduced from preclinical models and human disease are discussed. Topics span neurobiology and neuroprotection, pain-itch, inflammation, vascular and cardiac biology, pulmonary and airway function, skin, gastrointestinal tract, renal-urinary and uterine biology, skeletal and connective tissue, metabolism, stem cell biology, tissue engineering, cancer, basic ion channel biology, and hereditary TRPV4 channelopathies affecting skeletal development and peripheral motor innervation. Therapeutic strategies-from small-molecule modulators to lipid nanoparticle-delivered gene silencing-are discussed in the context of examples of endothelial translational paradigms, furthermore TRPV4's impact on sensory function including pain and itch. A brief personal reflection on the discovery of TRPV4 concludes this Systematic Review.