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Symbol TRPV4 contributors: mct/ - updated : 09-10-2017
HGNC name transient receptor potential cation channel, subfamily V, member 4
HGNC id 18083
Corresponding disease
BCYM3 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
    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
    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
    Type widely
       expressed in (based on citations)
    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
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningepidermis   Homo sapiens
    Epithelialbarrier liningretinal pigment epithelium (RPE)   Homo sapiensFetal
    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
    at STAGE
  • 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
    interspecies homolog to Drosophila transient receptor potential 12
    homolog to murine vanilloid receptor related
  • 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,cytoplasm,organelle,endoplasmic reticulum
  • 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
  • TRPV4 channel function may be modulated by TUBB and ANXA2 and their interactions may play a role in the mechanosensation in the pathogenesis of neuropathic pain
  • 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
  • role of TRPV4 as a cell-autonomous mediator for both the thermogenic and proinflammatory programs in adipocytes
  • 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
  • likely AKAP5, PRKCA, and TRPV4 channels form dynamic subcellular signaling domains that control Ca(2+) influx into arterial myocytes
  • regulation of systemic osmotic pressure
  • ion transport
    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
    small molecule
  • 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
  • MLC1 functionally interacts with the transient receptor potential vanilloid-4 cation channel (TRPV4) to increase intracellular calcium influx in response to hyposmosis
  • interaction between TRPV4 and tubulin beta 5 by associating together
  • 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)
  • up-regulation of FST in chondrocytes by skeletal dysplasia-inducing TRPV4 mutations contributes to disease pathogenesis
  • ELANE activates protease-activated receptor-2 (F2RL1) and transient receptor potential vanilloid 4 (TRPV4) to cause inflammation and pain
  • Ca2+ influx through the TRPV4 channel regulates FLII-MYH9 interaction, which in turn enables generation of the cell extensions essential for collagen remodeling
  • ZC4H2 is a positive modulator of TRPV4
  • cell & other
    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
    corresponding disease(s) BCYM3 , 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
  • 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
    Therapy target
    selectively disrupting the folding-sensitive region may present therapeutic potential for treating overactive TRPV4-mediated diseases, such as pain
    selectively disrupting the folding-sensitive region may present therapeutic potential for treating overactive TRPV4-mediated diseases, such as skeletal dysplasias
    . possibility that manipulating TRPV4 function would be useful to improve skin barrier function, especially where the cornified layer-dependent barrier is damaged
    diabetetype 2 
    TRPV4 is a very promising target for treating obesity and type 2 diabetes
  • 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
  • pharmacological inhibition of Trpv4 in mice modulate both thermogenic and proinflammatory pathways in fat, resulting in a robust resistance to obesity and insulin resistance