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1.A.4.2.5
Vanilloid receptor-related, osmotically activated channel, VR-OAC (also called TRPV4, VRL2, VROAC and Trp12); required for bladder voiding in mice (Gevaert et al., 2007). Regulated by Pacsin3 via its SH3 domain which affects its subcellular localization and inhibits its activity in a stimulus-specific fashion (D'hoedt et al., 2008). Responsible for autosomal dominant brachyolmia (Rock et al., 2008). Multiple gating mechanisms have been demonstrated for TRPV4 (Loukin et al., 2010). TRPV4 Ca2+ signalling regulates endothelial vascular function (Sonkusare et al., 2012) and adipose oxidative metabolism, inflammation and energy homeostasis (Ye et al. 2012).  H2O2 induces Ca2+ influx into microvascular endothelial cells via TrpV4 (Suresh et al. 2015). TrpV4 orthologs are volume-sensors, rather than osmo-sensors (Toft-Bertelsen et al. 2017) that mediate fluid secretion by the ciliary body. They are important for vertebrate vision by providing nutritive support to the cornea and lens, and by maintaining intraocular pressure (Jo et al. 2016). Interacts with the A-kinase anchor protein 5 (AKAP5 or AKAP79 of 427 aas; TC# 8.A.28.1.6; P24588) (Mack and Fischer 2017). Mutations in TRPV4 are associated with accelerated chondrogenic differentiation of dental pulp stem cells (Nonaka et al. 2019). The homolog in Cynops pyrrhogaster (85% identical) is inhibited by RN1734 and may play a role in the sperm acrosome reaction (Kon et al. 2019). TRPV4 antagonism attenuates aortic inflammation and remodeling via decreased smooth muscle cell activation and neutrophil transendothelial migration (Shannon et al. 2020). It forms a tight complex with CD98hc (TC# 8.A.9.2.2) and beta1 integrin (TC# 9.B.87.1.8) in focal adhesions where mechanochemical conversion takes place. CD98hc knock down inhibits TRPV4-mediated calcium influx induced by mechanical forces, but not by chemical activators, thus confirming the mechanospecificity of this signaling response. Molecular analysis revealed that forces applied to beta1 integrin must be transmitted from its cytoplasmic C-terminus via the CD98hc cytoplasmic tail to the ankyrin repeat domain of TRPV4 in order to produce ultra-rapid, force-induced, channel activation within the focal adhesion (Potla et al. 2020). TRPV4 mutations, resulting in severe gain of function, cause mixed neuropathy and skeletal phenotypes in humans (Taga et al. 2022). Cell swelling, heat, and chemical agonists use distinct pathways for the activation of TRPV4 (Vriens et al. 2004). Human TRPV4 is involved in immune activation, and because of its diverse engagement in the neuronal and immune systems, it is a potential therapeutic target for several immune-related disorders (Acharya et al. 2022). It is one of the major non-selective cation channel proteins that plays a crucial role in sensing biotic and abiotic stresses, such as pathogen infection, temperature, mechanical pressure and osmotic pressure changes by regulating Ca2+ homeostasis (He et al. 2022). The structure of human TRPV4 in complex with GTPase RhoAhas been determined, providing a template for the design of future therapeutics for treatment of TRPV4-related diseases (Nadezhdin et al. 2023). AQP4-independent TRPV4 modulation of plasma membrane water permeability has been documented (Barile et al. 2023). The possibility to tune plasma membrane water permeability more finely through TRPV4 might represent a protective mechanism in cells constantly facing severe osmotic challenges to avoid the potential deleterious effects of the rapid cell swelling occurring via AQP channels (Barile et al. 2023).  

Accession Number:Q9ERZ8
Protein Name:VROAC
Length:871
Molecular Weight:98010.00
Species:Rattus norvegicus (Rat) [10116]
Number of TMSs:7
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate calcium(2+)

Cross database links:

RefSeq: NP_076460.1   
Entrez Gene ID: 66026   
Pfam: PF00023    PF00520   
KEGG: rno:66026   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005886 C:plasma membrane
GO:0005262 F:calcium channel activity
GO:0005516 F:calmodulin binding
GO:0006816 P:calcium ion transport
GO:0006971 P:hypotonic response
GO:0055085 P:transmembrane transport

References (1)

[1] “Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor.”  Liedtke W.B.et.al.   11081638

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FASTA formatted sequence
1:	MADPGDGPRA APGDVAEPPG DESGTSGGEA FPLSSLANLF EGEEGSSSLS PVDASRPAGP 
61:	GDGRPNLRMK FQGAFRKGVP NPIDLLESTL YESSVVPGPK KAPMDSLFDY GTYRHHPSDN 
121:	KRWRRKVVEK QPQSPKAPAP QPPPILKVFN RPILFDIVSR GSTADLDGLL SYLLTHKKRL 
181:	TDEEFREPST GKTCLPKALL NLSNGRNDTI PVLLDIAERT GNMREFINSP FRDIYYRGQT 
241:	ALHIAIERRC KHYVELLVAQ GADVHAQARG RFFQPKDEGG YFYFGELPLS LAACTNQPHI 
301:	VNYLTENPHK KADMRRQDSR GNTVLHALVA IADNTRENTK FVTKMYDLLL LKCSRLFPDS 
361:	NLETVLNNDG LSPLMMAAKT GKIGVFQHII RREVTDEDTR HLSRKFKDWA YGPVYSSLYD 
421:	LSSLDTCGEE VSVLEILVYN SKIENRHEML AVEPINELLR DKWRKFGAVS FYINVVSYLC 
481:	AMVIFTLTAY YQPLEGTPPY PYRTTVDYLR LAGEVITLLT GVLFFFTSIK DLFMKKCPGV 
541:	NSLFVDGSFQ LLYFIYSVLV VVSAALYLAG IEAYLAVMVF ALVLGWMNAL YFTRGLKLTG 
601:	TYSIMIQKIL FKDLFRFLLV YLLFMIGYAS ALVTLLNPCT NMKVCNEDQS NCTVPSYPAC 
661:	RDSETFSAFL LDLFKLTIGM GDLEMLSSAK YPVVFILLLV TYIILTFVLL LNMLIALMGE 
721:	TVGQVSKESK HIWKLQWATT ILDIERSFPV FLRKAFRSGE MVTVGKSSDG TPDRRWCFRV 
781:	DEVNWSHWNQ NLGIINEDPG KSEIYQYYGF SHTMGRLRRD RWSSVVPRVV ELNKNSGTDE 
841:	VVVPLDNLGN PNCDGHQQGY APKWRAEDAP L