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FLASH GENE
Symbol TRPV4 contributors: mct/ - updated : 09-10-2013
HGNC name transient receptor potential cation channel, subfamily V, member 4
HGNC id 18083
Corresponding disease
BCYOL3 brachyolmia type 3
CBSMA congenital non-progressive (benign), spinal muscular atrophy
CMT2C Charcot-Marie-Tooth disease, axonal, type 2C
FDAB digital arthropathy-brachydactyly, familial
METTD metatropic dysplasia
PSMQ2 pseudo-Morquio syndrome type 2
SMDK spondylometaphyseal dysplasia Kozlowski type
SPSMA amyotrophy, neurogenic scapuloperoneal, New England type
Location 12q24.11      Physical location : 110.220.892 - 110.271.212
Synonym name
  • vanilloid receptor-related osmotically activated channel
  • OSM9-like transient receptor potential channel 4
  • osmosensitive transient receptor potential channel 4
  • vanilloid receptor-like protein 2
  • transient receptor potential protein 12
  • Synonym symbol(s) TRP12, VRL2, VROAC, OTRPC4, VR-OAC, VRL-2
    DNA
    TYPE functioning gene
    STRUCTURE 50.32 kb     16 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    LOC196469 12q24.11 similar to apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G; phorbolin-like protein MDS019 CMKLR1 12q24.1 chemokine-like receptor 1 HYPE 12q24.1 chemokine-like receptor 1 SART3 12q24.1 squamous cell carcinoma antigen recognised by T cells 3 NIFU 12-q24.1 squamous cell carcinoma antigen recognised by T cells 3 LOC338773 12q24.12 hypothetical protein LOC338773 SELPLG 12q24 selectin P ligand CORO1C 12q24.1 coronin, actin binding protein, 1C SSH1 12q24.12 slingshot 1 DAO 12q24.12 D-amino-acid oxidase DKFZp761H039 12q24.12 hypothetical protein DKFZp761H039 USP30 12q23.3 ubiquitin specific protease 30 LOC121642 12q24.12 similar to hypothetical protein 9530023G02 UNG 12q23-q24.1 uracil-DNA glycosylase LOC387883 12 LOC387883 ACACB 12q24.1 acetyl-Coenzyme A carboxylase beta FOXN4 12q24.12 forkhead box N4 LOC387884 12 LOC387884 FLJ37587 12q24.12 hypothetical protein FLJ37587 KCTD10 12q24.12 potassium channel tetramerisation domain containing 10 UBE3B 12q24.12 potassium channel tetramerisation domain containing 10 MMAB MVK 12q24 mevalonate kinase (mevalonic aciduria) MGC14436 12q24.12 hypothetical protein MGC14436 FLJ14721 12q24.12 hypothetical protein FLJ14721 TRPV4 12q24.1 transient receptor potential cation channel, subfamily V, member 4 GLTP 12q24.12 glycolipid transfer protein MGC10854 12q24.12 hypothetical protein MGC10854 GIT2 12q24.1 G protein-coupled receptor kinase-interactor 2 ANKRD13 12q24.12 ankyrin repeat domain 13 LOC144705 12q24.12 hypothetical gene supported by AF086409 CDV-1 12q24.13 carnitine deficiency-associated gene expressed in ventricle 1 ATP2A2 12q24.1 ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 HMGA1L3 12q24.13 high mobility group AT-hook 1-like 3 ARPC3 12q24 actin related protein 2/3 complex, subunit 3, 21kDa MGC14560 12q24.13 protein x 0004 HSU79274 12q24.13 protein predicted by clone 23733 VPS29 12q24 vacuolar protein sorting 29 (yeast) RAD9B 12q24.13 RAD9 homolog B (S. cerevisiae) TA-PP2C 12q24.13 T-cell activation protein phosphatase 2C FLJ21127 12q24.13 hypothetical protein FLJ21127 MGC15619 12q24.13 hypothetical protein MGC15619 PPP1CC 12q24.1 protein phosphatase 1, catalytic subunit, gamma isoform FLJ35843 12q24.13 hypothetical protein FLJ35843 MYL2 12q23-q24.3 myosin, light polypeptide 2, regulatory, cardiac, slow CUTL2 12q24.12 cut-like 2 (Drosophila)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 splicing 3250 - 871 - 2007 17374521
    reach the plasma membrane where they produce functional channels
    14 splicing 3012 - 811 - 2006 16293632
  • lacking an alternative exon (lacking exon 7)
  • retained in the ER
  • inability to oligomerize
  • 14 splicing 3051 - 824 - 2006 16293632
  • lacks exon 5
  • retained in the ER
  • inability to oligomerize
  • 16 splicing 3059 - 837 - 2006 16293632
  • a short deletion inside exon 2
  • reach the plasma membrane where they produce functional channels
  • exported to the plasma membrane like the full-length channel (871 AA) and was also functional
  • 13 splicing 2871 - 764 - 2006 16293632
  • double alternative splicing lacking exons 5 and 7
  • retained in the ER
  • inability to oligomerize
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Nervousbrain     Homo sapiens
     gangliasensory ganglia  highly Homo sapiensFetal
     nervespinal nerve  highly Homo sapiensFetal
    Respiratorylung   highly Homo sapiens
     nose   highly Homo sapiens
     respiratory tracttrachea  highly Homo sapiens
    Skin/Tegumentskin   highly Homo sapiens
    Urinarykidneynephron  highly Homo sapiens
     kidneytubulecollecting duct   Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningepidermis   Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    Nervousastrocyte Homo sapiens
    Nervousneuron Homo sapiens
    not specificchondrocyte Homo sapiens
    Respiratoryepithelial cell Homo sapiens
    Skin/Tegumentkeratinocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • three ANK repeats at the N terminus, necessary for oligomerization of TRPV4, found to bind to the armadillo repeat domain of CTNNB1
  • a proline-rich N-terminal region important for the interaction with PACSIN 3, that does not have a counterpart in other members of the TRPV subfamily
  • six predicted membrane-spanning domain and a putative pore loop
  • a cation conductivity pore between transmembrane domains 5 and 6
  • C-terminal intracellular tailsrequired for oligomerization, which takes place in the ER and precedes plasma membrane trafficking , having a role in modulating protein folding, trafficking, and activity
  • mono polymer homomer , tetramer
    HOMOLOGY
    interspecies homolog to Drosophila transient receptor potential 12
    homolog to murine vanilloid receptor related
    Homologene
    FAMILY
  • vanilloid family of Ca(2+) channels
  • TrpV subfamily
  • transient receptor potential (TRP) of ion channel
  • CATEGORY transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane,junction,adherens
        intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    text
  • functional interaction with PACSIN3 could be important in cell types that show distribution of both proteins to the same subcellular regions such as renal tubule cells where the proteins are associated with the luminal plasma membrane
  • all deletions upstream of AA 828 resulted in total ER retention that could not rescued by coexpression with the full-length protein
  • specifically localized with AJ components at the plasma membrane
  • strongly expressed in astrocytic endfeet membranes abutting the pia
  • forms a homotetramer within the endoplasmic reticulum (ER)
  • basic FUNCTION
  • Ca2+ permeable, non selective cation channel, be involved in the regulation of systemic osmotic pressure
  • may be playing a role in the regulation of body osmolarity, mechanosensation, temperature sensing, vascular regulation and, possibly, hearing
  • regulates the SOX9 pathway and contributes to the process of chondrogenesis
  • displays a widespread expression in various cells and tissues and has been implicated in diverse physiological processes, including osmotic homeostasis, thermo- and mechanosensation, vasorelaxation, tuning of neuronal excitability, and bladder voiding
  • has a functional role in keratinocyte cell volume regulation
  • plays a crucial role in regulating airway epithelial barrier function, epithelial and endothelial permeability, smooth muscle contraction and mucociliary transport
  • mediate Ca2+ influx (assumed to act as a trigger of regulatory volume decrease) in response to osmotic stress
  • contains an additional voltage-dependent gating mechanism in series with the main intracellular gate
  • having a role in the development and maturation of cell-cell junctions in epithelia of the skin
  • involved in the actin remodeling, which is important for development and maturation of cell-cell contacts induced by the Ca2+ switch
  • plays an important role in the formation and/or maintenance of functional intercellular barriers
  • its activation leads to a retraction of the lamellipodia and to a decrease in migratory behaviour
  • TRPV4 and AQP4 combined possess the essential features expected of a regulatory volume decrease (RVD) activator
  • mediates neurotrophic factor-driven neuritogenesis in peripheral neurons
  • is essential for axonal growth of sensory/motor nerves in early development as well as for their maintenance in the adult
  • important role in epidermal barrier function in human skin keratinocytes
  • mediates Ca(2+) influx in the late stage of osteoclast differentiation and thereby regulates Ca(2+) signaling
  • is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis
  • functional status of TRPV4, which underlies mechanosensitive Ca(2+) signaling in collecting duct cells, inversely correlates with renal cystogenesis in ARPKD (autosomal recessive polycystic kidney disease)
  • endothelial TRPV4 channels mediate dilation of cerebral arteries
  • role for TRPV4 finger loop three in the physiological response
  • glial cell-expressed TRPV4 is a potential key factor responsible for infrasound-induced neuronal impairment
  • suggested to play a role in the regulation of ciliary beat frequency (CBF)
  • may participate in mucociliary clearance and airway protection
  • male-specific regulator of bone metabolism, a determinant of bone strength, and a potential risk predictor for fractures through regulation of bone matrix mineralization and intra-cortical porosity
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    text
  • regulation of systemic osmotic pressure
  • ion transport
  • PATHWAY
    metabolism
    signaling
    a component
  • TRPV4/AQP4 complex in astrocytes, that constitutes a key element in the brain volume homeostasis by acting as an osmosensor that couples osmotic stress to downstream signaling cascades
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with SOX9 and SOX6 (activation of TRPV4 increased the steady-state levels of SOX9 mRNA and protein and SOX6 mRNA)
  • interacting with OS9 (binds the juxtamembrane region in the N-terminal tail of TRPV4, prevents the polyubiquitination of TRPV4 at the ER and retards its transport through this compartment, playing a role in the regulation of TRPV4 biogenesis by holding and protecting its monomers from a premature polyubiquitination and proteasomal degradation)
  • MAP7 may enhance the membrane expression of TRPV4 and possibly link cytoskeletal microfilaments
  • interaction with PACSIN3
  • interacts with calmodulin
  • interacts with MAP7 and Src family Tyr protein kinases LYN, SRC, FYN, HCK, LCK and YES
  • interacts with CTNNB1, a crucial component linking adherens junctions and the actin cytoskeleton, thereby enhancing cell-cell junction development and formation of the tight barrier between skin keratinocytes
  • AQP4 and TRPV4 interact and colocalize physical (interaction of AQP4 with TRPV4 is essential for TRPV4 to function as an astroglial osmosensor)
  • PRKCA mediates agonist-induced receptor-mediated TRPV4 activation in endothelial cells
  • ANXA2 is associated with TRPV4 and regulates TRPV4-mediated Ca(2+) influx and substance P (SP) release in dorsal root ganglion neurons
  • F2RL1 activation generates a signal that induces sustained activation of TRPV4, which requires a key tyrosine residue (TRPV4-Tyr-110)
  • cell & other
    REGULATION
    activated by osmotically activated
    membrane stretch, by non-noxious warm temperatures and by a range of chemical activators
    low pH, citrate and phorbol esters
    inhibited by strongly inhibited by PACSIN3
    a genomic mechanism of estrogen action altering KCNE2 expression, which may have important physiological implications
    Other functionally regulated by WNK family kinases at the level of cell surface expression
    PKC and PKA enhance activation of TRPV4 by phosphorylation depending on the assembly by AKAP5 into a signaling complex
    phosphorylated on serine 824 (important role of this phosphorylation in TRPV4 sensitization and the development of hyperalgesia)
    regulated by PGR (involved in regulation of TRPV4 expression by progesterone)
    its activity is regulated by the binding of calmodulin and small molecules such as ATP to the ankyrin repeat domain (ARD) at its cytoplasmic N-terminus
    ASSOCIATED DISORDERS
    corresponding disease(s) BCYOL3 , SMDK , METTD , CMT2C , SPSMA , CBSMA , PSMQ2 , FDAB
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation     gain of function
    gain-of-function (GOF) mutations were found to cause autosomal dominant blockage of bone development
    Susceptibility
  • to chronic obstructive pulmonary disease (COPD)
  • to hyponatremia
  • Variant & Polymorphism other
  • polymorphisms in the TRPV4 gene are associated with COPD
  • nonsynonymous polymorphismis associated with hyponatremia
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    miscelleaneouspain 
    selectively disrupting the folding-sensitive region may present therapeutic potential for treating overactive TRPV4-mediated diseases, such as pain
    osteoarticularbone 
    selectively disrupting the folding-sensitive region may present therapeutic potential for treating overactive TRPV4-mediated diseases, such as skeletal dysplasias
    dermatologyskin 
    . possibility that manipulating TRPV4 function would be useful to improve skin barrier function, especially where the cornified layer-dependent barrier is damaged
    ANIMAL & CELL MODELS
  • TRPV4-deficient mice displayed impairment of the intercellular junction-dependent barrier function in the skin
  • chondrocytes from Trpv4-null mice do not respond to hypo-osmotic stress suggesting that the mechanosensory role of TRPV4 is important in articular cartilage