TRPV4

Last updated
TRPV4
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TRPV4 , BCYM3, CMT2C, HMSN2C, OTRPC4, SMAL, SPSMA, SSQTL1, TRP12, VRL2, VROAC, transient receptor potential cation channel subfamily V member 4
External IDs OMIM: 605427; MGI: 1926945; HomoloGene: 11003; GeneCards: TRPV4; OMA:TRPV4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

59341

63873

Ensembl

ENSG00000111199

ENSMUSG00000014158

UniProt

Q9HBA0

Q9EPK8

RefSeq (mRNA)

NM_001177428
NM_001177431
NM_001177433
NM_021625
NM_147204

Contents

NM_022017

RefSeq (protein)

NP_001170899
NP_001170902
NP_001170904
NP_067638
NP_671737

NP_071300

Location (UCSC) Chr 12: 109.78 – 109.83 Mb Chr 5: 114.76 – 114.8 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the TRPV4 gene.

The TRPV4 gene encodes TRPV4, initially named "vanilloid-receptor related osmotically activated channel" (VR-OAC) and "OSM9-like transient receptor potential channel, member 4 (OTRPC4)", [5] [6] a member of the vanilloid subfamily in the transient receptor potential (TRP) superfamily of ion channels. [7] [8] [9] The encoded protein is a Ca2+-permeable, nonselective cation channel that has been found involved in multiple physiologic functions, dysfunctions and also disease. It functions in the regulation of systemic osmotic pressure by the brain, in vascular function, in liver, intestinal, renal and bladder function, in skin barrier function and response of the skin to ultraviolet-B radiation, in growth and structural integrity of the skeleton, in function of joints, in airway- and lung function, in retinal and inner ear function, and in pain. The channel is activated by osmotic, mechanical and chemical cues. It also responds to thermal changes (warmth). Channel activation can be sensitized by inflammation and injury.

The TRPV4 gene has been co-discovered by W. Liedtke et al. [5] and R. Strotmann et al. [6]

Clinical significance

Channelopathy mutations in the TRPV4 gene lead to skeletal dysplasias, premature osteoarthritis, and neurological motor function disorders and are associated with a range of disorders, including brachyolmia type 3, congenital distal spinal muscular atrophy, Familial digital arthropathy-brachydactyly (FDAB), [10] scapuloperoneal spinal muscular atrophy, and subtype 2C of Charcot–Marie–Tooth disease. [11]

Pharmacology

A number of TRPV4 agonists and antagonists have been identified since its discovery. [12] The discovery of unselective modulators (e.g. antagonist ruthenium red) was followed by the apparition of more potent (agonist 4aPDD) [13] or selective (antagonist RN-1734) [14] compounds, including some with bioavailability suitable for in vivo pharmacology studies such as agonist GSK1016790A [15] (with ~10 fold selectivity vs TRPV1), and antagonists HC-067047 [16] (with ~5 fold selectivity vs hERG and ~10 fold selectivity vs TRPM8) and RN-9893 [17] (with ~50 fold selectivity vs TRPM8 and ~10 fold selectivity vs M1).

Resolvin D1 (RvD1), a metabolite of the omega 3 fatty acid, docosahexaenoic acid, is a member of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, humans. This SPM also dampens pain perception arising from various inflammation-based causes in animal models. The mechanism behind this pain-dampening effect involves the inhibition of TRPV4, probably (in at least certain cases) by an indirect effect wherein it activates another receptor located on neurons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which a SPM may operate to down-regulate TRPs and thereby pain perception. [18] [19] [20] [21] [22]

Interactions

TRPV4 has been shown to interact with MAP7 [23] and LYN. [24]

Implication in Temperature-Dependent Sex Determination in Reptiles

TRPV4 has been proposed to be the thermal sensor in gonads of Alligator mississipiensis , a species with temperature-dependent sex determination. [25] However the data were over interpreted and TRPV4 is probably not involved in temperature-dependent sex determination due to large overlap of expression at male producing temperature and female producing temperature for example.

See also

Related Research Articles

Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN, and TRPA. Group 2 consists of TRPP and TRPML. Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of taste, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (allicin), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of lipid-gated ion channels.

<span class="mw-page-title-main">WIN 55,212-2</span> Chemical compound

WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.

<span class="mw-page-title-main">TRPV</span> Subgroup of TRP cation channels named after the vanilloid receptor

TRPV is a family of transient receptor potential cation channels in animals. All TRPVs are highly calcium selective.

<span class="mw-page-title-main">Nociceptin receptor</span> Protein-coding gene in the species Homo sapiens

The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.

<span class="mw-page-title-main">TRPA1</span> Protein and coding gene in humans

Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 gene.

<span class="mw-page-title-main">TRPV2</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene. TRPV2 is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions, and responds to noxious temperatures greater than 52 °C. It has a structure similar to that of potassium channels, and has similar functions throughout multiple species; recent research has also shown multiple interactions in the human body.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.

<span class="mw-page-title-main">TRPM3</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.

<span class="mw-page-title-main">TRPV3</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.

<span class="mw-page-title-main">NAGly receptor</span> Protein-coding gene in the species Homo sapiens

N-Arachidonyl glycine receptor, also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene. Along with the other previously "orphan" receptors GPR55 and GPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors. It has been found to be involved in the regulation of intraocular pressure.

<span class="mw-page-title-main">Iodoresiniferatoxin</span> Chemical compound

Iodoresiniferatoxin (I-RTX) is a strong competitive antagonist of the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor. I-RTX is derived from resiniferatoxin (RTX).

Relief from chronic pain remains a recognized unmet medical need. Consequently, the search for new analgesic agents is being intensively studied by the pharmaceutical industry. The TRPV1 receptor is a ligand gated ion channel that has been implicated in mediation of many types of pain and therefore studied most extensively. The first competitive antagonist, capsazepine, was first described in 1990; since then, several TRPV1 antagonists have entered clinical trials as analgesic agents. Should these new chemical entities relieve symptoms of chronic pain, then this class of compounds may offer one of the first novel mechanisms for the treatment of pain in many years.

Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain. Zucapsaicin is a member of phenols and a member of methoxybenzenes. It is a modulator of transient receptor potential cation channel subfamily V member 1 (TRPV-1), also known as the vanilloid or capsaicin receptor 1 that reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use.

Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.

<span class="mw-page-title-main">GSK1016790A</span> Chemical compound

GSK1016790A is a drug developed by GlaxoSmithKline which acts as a potent and selective agonist for the TRPV4 receptor. It has been used to study the role of TRPV4 receptors in the function of smooth muscle tissue, particularly that lining blood vessels, lymphatic system, and the bladder.

<span class="mw-page-title-main">AMG-9810</span> Chemical compound

AMG-9810 is a drug which acts as a potent and selective antagonist for the TRPV1 receptor. It has analgesic and antiinflammatory effects and is used in scientific research, but has not been developed for medical use. It has high antagonist potency and good bioavailability and pharmacokinetics, and so has been used to study the role of TRPV1 in areas other than pain perception, such as its roles in the brain.

<span class="mw-page-title-main">HC-067047</span> Chemical compound

HC-067047 is a drug which acts as a potent and selective antagonist for the TRPV4 receptor. It has been used to investigate the role of TRPV4 receptors in a number of areas, such as regulation of blood pressure, bladder function and some forms of pain, as well as neurological functions.

<span class="mw-page-title-main">AMG-517</span> Chemical compound

AMG-517 is a drug which acts as a potent and selective blocker of the TRPV1 ion channel. It was developed as a potential treatment for chronic pain, but while it was an effective analgesic in animal studies it was dropped from human clinical trials at Phase I due to producing hyperthermia as a side effect, as well as poor water solubility. It is still used in scientific research into the function of the TRPV1 channel and its role in pain and inflammation, and has been used as a template for the design of several newer analogues which have improved properties.

<span class="mw-page-title-main">SB-705498</span> Chemical compound

SB-705498 is a drug which acts as a potent and selective blocker of the TRPV1 ion channel. It has been evaluated in clinical trials for the treatment of rhinitis and chronic cough.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000111199 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000014158 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Liedtke W, Choe Y, Martí-Renom MA, Bell AM, Denis CS, Sali A, et al. (October 2000). "Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor". Cell. 103 (3): 525–535. doi:10.1016/S0092-8674(00)00143-4. PMC   2211528 . PMID   11081638.
  6. 1 2 Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD (October 2000). "OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity". Nature Cell Biology. 2 (10): 695–702. doi:10.1038/35036318. PMID   11025659. S2CID   21148080.
  7. ↑ Clapham DE, Julius D, Montell C, Schultz G (December 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews. 57 (4): 427–450. doi:10.1124/pr.57.4.6. PMID   16382100. S2CID   17936350.
  8. ↑ Harteneck C, Plant TD, Schultz G (April 2000). "From worm to man: three subfamilies of TRP channels". Trends in Neurosciences. 23 (4): 159–166. doi:10.1016/S0166-2236(99)01532-5. PMID   10717675. S2CID   41074873.
  9. ↑ Plant TD, Strotmann R (2007). "TRPV4". Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology. Vol. 179. pp. 189–205. doi:10.1007/978-3-540-34891-7_11. ISBN   978-3-540-34889-4. PMID   17217058.
  10. ↑ Lamandé SR, Yuan Y, Gresshoff IL, Rowley L, Belluoccio D, Kaluarachchi K, et al. (October 2011). "Mutations in TRPV4 cause an inherited arthropathy of hands and feet". Nature Genetics. 43 (11): 1142–1146. doi:10.1038/ng.945. PMID   21964574. S2CID   27430401.
  11. ↑ Online Mendelian Inheritance in Man (OMIM): 605427
  12. ↑ Vincent F, Duncton MA (2011). "TRPV4 agonists and antagonists". Current Topics in Medicinal Chemistry. 11 (17): 2216–2226. doi:10.2174/156802611796904861. PMID   21671873.
  13. ↑ Watanabe H, Davis JB, Smart D, Jerman JC, Smith GD, Hayes P, et al. (April 2002). "Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives". The Journal of Biological Chemistry. 277 (16): 13569–13577. doi: 10.1074/jbc.M200062200 . PMID   11827975.
  14. ↑ Vincent F, Acevedo A, Nguyen MT, Dourado M, DeFalco J, Gustafson A, et al. (November 2009). "Identification and characterization of novel TRPV4 modulators". Biochemical and Biophysical Research Communications. 389 (3): 490–494. doi:10.1016/j.bbrc.2009.09.007. PMID   19737537.
  15. ↑ Thorneloe KS, Sulpizio AC, Lin Z, Figueroa DJ, Clouse AK, McCafferty GP, et al. (August 2008). "N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I". The Journal of Pharmacology and Experimental Therapeutics. 326 (2): 432–442. doi:10.1124/jpet.108.139295. PMID   18499743. S2CID   517735.
  16. ↑ Everaerts W, Zhen X, Ghosh D, Vriens J, Gevaert T, Gilbert JP, et al. (November 2010). "Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis". Proceedings of the National Academy of Sciences of the United States of America. 107 (44): 19084–19089. Bibcode:2010PNAS..10719084E. doi: 10.1073/pnas.1005333107 . PMC   2973867 . PMID   20956320.
  17. ↑ Wei ZL, Nguyen MT, O'Mahony DJ, Acevedo A, Zipfel S, Zhang Q, et al. (September 2015). "Identification of orally-bioavailable antagonists of the TRPV4 ion-channel". Bioorganic & Medicinal Chemistry Letters. 25 (18): 4011–4015. doi:10.1016/j.bmcl.2015.06.098. PMID   26235950.
  18. ↑ Qu Q, Xuan W, Fan GH (January 2015). "Roles of resolvins in the resolution of acute inflammation". Cell Biology International. 39 (1): 3–22. doi:10.1002/cbin.10345. PMID   25052386. S2CID   10160642.
  19. ↑ Serhan CN, Chiang N, Dalli J, Levy BD (October 2014). "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology. 7 (2): a016311. doi:10.1101/cshperspect.a016311. PMC   4315926 . PMID   25359497.
  20. ↑ Lim JY, Park CK, Hwang SW (2015). "Biological Roles of Resolvins and Related Substances in the Resolution of Pain". BioMed Research International. 2015: 830930. doi: 10.1155/2015/830930 . PMC   4538417 . PMID   26339646.
  21. ↑ Ji RR, Xu ZZ, Strichartz G, Serhan CN (November 2011). "Emerging roles of resolvins in the resolution of inflammation and pain". Trends in Neurosciences. 34 (11): 599–609. doi:10.1016/j.tins.2011.08.005. PMC   3200462 . PMID   21963090.
  22. ↑ Serhan CN, Chiang N, Dalli J (May 2015). "The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution". Seminars in Immunology. 27 (3): 200–215. doi:10.1016/j.smim.2015.03.004. PMC   4515371 . PMID   25857211.
  23. ↑ Suzuki M, Hirao A, Mizuno A (December 2003). "Microtubule-associated [corrected] protein 7 increases the membrane expression of transient receptor potential vanilloid 4 (TRPV4)". The Journal of Biological Chemistry. 278 (51): 51448–51453. doi: 10.1074/jbc.M308212200 . PMID   14517216.
  24. ↑ Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM (March 2003). "Regulation of a transient receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinase-dependent tyrosine phosphorylation of TRPV4 on TYR-253 mediates its response to hypotonic stress". The Journal of Biological Chemistry. 278 (13): 11520–11527. doi: 10.1074/jbc.M211061200 . PMID   12538589.
  25. ↑ Yatsu R, Miyagawa S, Kohno S, Saito S, Lowers RH, Ogino Y, Fukuta N, Katsu Y, Ohta Y, Tominaga M, Guillette LJ, Iguchi T (2015). "TRPV4 associates environmental temperature and sex determination in the American alligator". Sci Rep. 5: 18581. Bibcode:2015NatSR...518581Y. doi: 10.1038/srep18581 . PMC   4683465 . PMID   26677944.

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