Selected-GenAtlas references	SOURCE	GeneCards	NCBI Gene	Swiss-Prot	Orphanet	Ensembl
	HGNC	UniGene	Nucleotide	OMIM		UCSC

Home Page

FLASH GENE

Symbol

TRPV4

contributors: mct/ - updated : 10-10-2009

HGNC name	transient receptor potential cation channel, subfamily V, member 4
HGNC id	18083

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_021625 16 splicing 3250 NP_067638 - 871 - 2007 17374521 reach the plasma membrane where they produce functional channels NM_147204 14 splicing 3012 NP_671737 - 811 - 2006 16293632 lacking an alternative exon (lacking exon 7) retained in the ER inability to oligomerize NM_001177428 14 splicing 3051 NP_001170899 - 824 - 2006 16293632 lacks exon 5 retained in the ER inability to oligomerize NM_001177431 16 splicing 3059 NP_001170902 - 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 NM_001177433 13 splicing 2871 NP_001170904 - 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)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive mouth tongue     highly Endocrine neuroendocrine pituitary     highly Reproductive male system testis     highly Respiratory lung       highly   respiratory tract trachea     highly Skin/Tegument skin       highly Homo sapiens Urinary kidney tubule convoluted tubule distal tubule highly   kidney nephron

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier lining epidermis     Homo sapiens Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous astrocyte Homo sapiens Nervous neuron Homo sapiens not specific chondrocyte Homo sapiens Skin/Tegument keratinocyte 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

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
	role for TRPV4 finger loop three in the physiological response.

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)
	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

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)

ASSOCIATED DISORDERS

corresponding disease(s)

BCYOL3 , SMDK , METTD , CMT2C , SPSMA , CBSMA , PSMQ2 , FDAB

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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	modulation of TRPV4 activity using calcium channel inhibitors could represent an avenue for treatment
	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