TRPV4 (transient receptor potential cation channel subfamily V member 4; HGNC:18083, NCBI Gene ID 59341) is a human locus mapped to chromosome band 12q24.11 that encodes TRPV4 non-selective Ca2+-permeable cation channel (871 aa). TRPV4 acts in osmosensation, shear-stress mechanotransduction & skeletal dysplasia, together with TRPV1 Vanilloid Receptor, PIEZO1 Mechanosensitive Channel Gene, and PIEZO2 Mechanosensitive Channel Gene. Encodes a polymodal Ca2+-permeable TRP channel activated by osmotic cell swelling, warmth, and mechanical shear stress.
Charcot-Marie-Tooth disease type 2C, metatropic dysplasia & brachyolmia
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 15-exon gene on chromosome 12q24.11 encoding an 871-amino-acid subunit that assembles into homotetrameric channels featuring six N-terminal ankyrin repeat domains, six transmembrane helices (S1–S6), and a Ca2+-selective pore loop between S5 and S6.
Biochemical & Physiological Mechanism: Gates extracellular calcium influx in response to hypotonic cell swelling, physiological warm temperatures (27–35 degrees C), fluid shear stress, and epoxyeicosatrienoic acid (EET) lipid metabolites derived from arachidonic acid, coupling mechanical forces to endothelial nitric oxide synthase (NOS3) activation and vasodilation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Heterozygous missense mutations in the ankyrin repeat and transmembrane domains cause a broad spectrum of dominant skeletal dysplasias (brachyolmia, spondyloepiphyseal dysplasia Maroteaux type, and lethal metatropic dysplasia) as well as axonal neuropathies including Charcot-Marie-Tooth disease type 2C and scapuloperoneal spinal muscular atrophy.
Therapeutic & Clinical Pharmacology: Clinical TRPV4 antagonists (such as GSK2798745) have been evaluated for cardiogenic pulmonary edema, cough, and osteoarthritis, while channel modulation is studied in peripheral neuropathic pain.