TRPV1

From Wikipedia, the free encyclopedia
  (Redirected from Vanilloid receptor subtype 1)
Jump to: navigation, search
transient receptor potential cation channel, subfamily V, member 1
Trpv1 pip2 bilayer.png
Homology model of the TRPV1 ion channel tetramer (where the monomers are individually colored cyan, green, blue, and magenta respective) imbedded in a cartoon representation of a lipid bilayer. PIP2 signaling ligands are represented by space-filling models (carbon = white, oxygen = red, phosphorous = orange).[1]
Identifiers
Symbols TRPV1 ; DKFZp434K0220; VR1
External IDs OMIM602076 MGI1341787 HomoloGene12920 IUPHAR: TRPV1 ChEMBL: 4794 GeneCards: TRPV1 Gene
RNA expression pattern
PBB GE TRPV1 219632 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7442 193034
Ensembl ENSG00000196689 ENSMUSG00000005952
UniProt Q8NER1 Q3V318
RefSeq (mRNA) NM_018727 NM_001001445
RefSeq (protein) NP_061197 NP_001001445
Location (UCSC) Chr 17:
3.42 – 3.45 Mb
Chr 11:
73.05 – 73.08 Mb
PubMed search [1] [2]

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.[2][3] This protein is a member of the TRPV group of transient receptor potential family of ion channels.[4]

The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides sensation of scalding heat and pain (nociception).

Function[edit]

TRPV1 is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best-known activators of TRPV1 are: temperature greater than 43 °C (109 °F); acidic conditions; capsaicin, the irritating compound in hot chilli peppers; allyl isothiocyanate, the pungent compound in mustard and wasabi.[5] The activation of TRPV1 leads to a painful, burning sensation. Its endogenous activators include: low pH (acidic conditions), the endocannabinoid anandamide, N-oleyl-dopamine, and N-arachidonoyl-dopamine. TRPV1 receptors are found mainly in the nociceptive neurons of the peripheral nervous system, but they have also been described in many other tissues, including the central nervous system. TRPV1 is involved in the transmission and modulation of pain (nociception), as well as the integration of diverse painful stimuli.[6][7]

Sensitization[edit]

The sensitivity of TRPV1 to noxious stimuli, such as high temperatures, is not static. Upon tissue damage and the consequent inflammation, a number of inflammatory mediators, such as various prostaglandins and bradykinin, are released. These agents increase the sensitivity of nociceptors to noxious stimuli. This manifests as an increased sensitivity to painful stimuli (hyperalgesia) or pain sensation in response to non-painful stimuli (allodynia). Most sensitizing pro-inflammatory agents activate the phospholipase C pathway. Phosphorylation of TRPV1 by protein kinase C have been shown to play a role in sensitization of TRPV1. The cleavage of PIP2 by PLC-beta can result in disinhibiton of TRPV1 and, as a consequence, contribute to the sensitivity of TRPV1 to noxious stimuli.

Desensitization[edit]

Upon prolonged exposure to capsaicin, TRPV1 activity decreases, a phenomenon called desensitization. Extracellular calcium ions are required for this phenomenon, thus influx of calcium and the consequential increase of intracellular calcium mediate this effect. Various signaling pathways such as calmodulin and calcineurin, and the decrease of PIP2, have been implicated in desensitization of TRPV1. Desensitization of TRPV1 is thought to underlie the paradoxical analgesic effect of capsaicin.

Clinical significance[edit]

Peripheral nervous system[edit]

Treatment of pain is an unmet medical need costing billions of dollars every year. As a result of its involvement in nociception, TRPV1 has been a prime target for the development of novel pain reducers (analgesics). Two major strategies have been used:

Antagonists[edit]

Antagonists block TRPV1 activity, thus reducing pain. Identified antagonists include the competitive antagonist capsazepine and the non-competitive antagonist ruthenium red.[2] These agents could be useful when applied systemically.[8] Numerous TRPV1 antagonists have been developed by pharmaceutical companies. TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats.[9] This provides evidence that TRPV1 is capsaicin's sole receptor.[10] In humans, drugs acting at TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis.[11]

The major roadblock for the usefulness of these drugs is their effect on body temperature (hyperthermia). The role of TRPV1 in the regulation of body temperature has emerged in the last few years. Based on a number of TRPV-selective antagonists' causing an increase in body temperature (hyperthermia), it was proposed that TRPV1 is tonically active in vivo and regulates body temperature[12] by telling the body to "cool itself down". Without these signals, the body overheats. Likewise, this explains the propensity of capsaicin (a TRPV1 agonist) to cause sweating (i.e.: a signal to reduce body temperature). In a recent report, it was found that tonically active TRPV1 channels are present in the viscera and keep an ongoing suppressive effect on body temperature.[13] Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance [14] Experiments have shown that TRPV1 blockade increases body temperature in multiple species, including rodents and humans, suggesting that TRPV1 is involved in body temperature maintenance.[12] Recently, AMG 517, a highly selective TRPV1 antagonist was dropped out of clinical trials due to the undesirable level of hyperthermia.[15] A second molecule, SB-705498, was also evaluated in the clinic but its effect on body temperature was not reported.[16] Recently, it was disclosed that clinical trials of two more TRPV1 antagonists, GRC 6211 and NGD 8243, have been stopped. Post translational modification of TRPV1 protein by its phosphorylation is critical for its functionality. Recent reports published from NIH suggest that Cdk5-mediated phosphorylation of TRPV1 is required for its ligand-induced channel opening.[17]

Agonists[edit]

Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, upon prolonged application, TRPV1 activity would decrease (desensitization), leading to alleviation of pain. Agonists can be applied locally to the painful area as through a patch or an ointment. Numerous capsaicin-containing creams are available over the counter, containing low concentrations of capsaicin (0.025 - 0.075%). It is debated whether these preparations actually lead to TRPV1 desensitization; it is possible that they act via counter-irritation. Novel preparations containing higher capsaicin concentration (up to 10%) are under clinical trials.[18] 8% capsaicin patches have recently become available for clinical use, with supporting evidence demonstrating that a 30-minute treatment can provide up to 3 months analgesia by causing regression of TRPV1-containing neurons in the skin.[19]

Fatty acid conjugates[edit]

N-Arachidonoyl dopamine, a endocannabinoid found in the human CNS, structurally similar to capsaicin, activates the TRPV1 channel with an EC50 of approximately of 50 nM. [7]

N-Oleyl-dopamine, another endogenous agonist, binds bind to human VR1 with an Ki of 36 Nm.[20]

Another endocannabinoid anandamide has also been shown to act on TRPV1 receptors.[21]

AM404—an active metabolite of paracetamol—that serves as an anandamide reuptake inhibitor and COX inhibitor also serves as a potent TRPV1 agonist.[22]

The plant-biosynthesized cannabinoid cannabidiol also shows "either direct or indirect activation" of TRPV1 receptors.[23]

Central nervous system[edit]

TRPV1 is also expressed at high levels in the central nervous system and has been proposed as a target for treatment not only of pain but also for other conditions such as anxiety.[24] Furthermore, TRPV1 appears to mediate long-term depression (LTD) in the hippocampus.[25] LTD has been linked to a decrease in the ability to make new memories, unlike its opposite long-term potentiation (LTP), which aids in memory formation. A dynamic pattern of LTD and LTP occurring at many synapses provides a code for memory formation. Long-term depression and subsequent pruning of synapses with reduced activity is an important aspect of memory formation. In rat brain slices, activation of TRPV1 with heat or capsaicin induced LTD while capsazepine blocked capsaicin's ability to induce LTD.[25] In the brainstem (solitary tract nucleus), TRPV1 controls the asynchronous and spontaneous release of glutamate from unmyelinated cranial visceral afferents - release processes that are active at normal temperatures and hence quite distinct from TRPV1 responses in painful heat.[26] Hence, there may be therapeutic potential in modulating TRPV1 in the central nervous system, perhaps as a treatment for epilepsy (TRPV1 is already a target in the peripheral nervous system for pain relief).

Protein engineering[edit]

An example of modularity and that allow protein engineering is the heat activation domain. TRPV proteins are activated by heat on the C-terminus, while TRPM proteins are activated by cold temperatures (<23 to 28 °C (73 to 82 °F)) in the same location. Exchanging the C-terminals for each other, could then activate these proteins at different than normal temperatures.[27] Chemical genetics has also been used to introduce TRPV1 into cells that do not normally express it. When capsaicin is added, those cells are then activated by the influx of calcium. This system is not as fast as other controls, such as optogenetics, but remains an important mechanism of spatial and temporal control.[28] This method of control can be applied to a variety of systems and cells, and will most likely be expanded and improved in the near future.

The aforementioned capsaicin-activated TRPV1 model allows for transient, reversible, and sensitive control of neurons.[28] Even before the TRPV1 ion channel was identified, capsaicin has been used to conditionally activate nociceptors to study brain circuitry.[2] Recently, embryonic stem cell technology and chemical genetics have allowed for the production of mice genetically engineered to express TRPV1 upon Cre recombinase-mediated recombination in non-nociceptive neurons. Upon treatment with a lentiviral vector engineered to express Cre, TRPV1 is expressed and consequently, treatment with capsaicin results in the production of inward currents in the targeted neurons. No capsaicin-induced currents are observed in TRPV1-expressing non-virally treated mice.[28]

Breeding the TRPV1-expressing mice with mice expressing a transgenic nestin-Cre promoter yields a population of offspring that express both TRPV1 and Cre. Upon infusion with capsaicin, these mice exhibit capsaicin-induced action potential firings. As expected by the researchers, the offspring that express only TRPV1 show no response to capsaicin. It was further shown that this model can be reproduced in other types of neurons, generating similar results. Also, it can be used in vitro or in vivo to show the effects of capsaicin treatment in awake TRPV1-Cre-expressing mice. This technology provides another system in which mammalian circuitry may be studied, especially because it may be used to activate structures inaccessible to light, which are impossible to examine using optogenetic techniques.[28]

Interactions[edit]

TRPV1 has been shown to interact with:

Discovery[edit]

The dorsal root ganglion (DRG) neurons of mammals were known to express a heat-sensitive ion channel that could be activated by capsaicin.[31] The research group of David Julius, therefore, created a cDNA library of genes expressed in dorsal root ganglion neurons, expressed the clones in HEK 293 cells, and looked for cells that respond to capsaicin with calcium influx (which HEK-293 normally not do). After several rounds of screening and dividing the library, a single clone encoding the TRPV1 channel was finally identified in 1997. It was the first TRPV channel to be identified.[2]

See also[edit]

References[edit]

  1. ^ Brauchi S, Orta G, Mascayano C, Salazar M, Raddatz N, Urbina H, Rosenmann E, Gonzalez-Nilo F, Latorre R (2007). "Dissection of the components for PIP2 activation and thermosensation in TRP channels". Proceedings of the National Academy of Sciences of the United States of America 104 (24): 10246–51. doi:10.1073/pnas.0703420104. PMC 1891241. PMID 17548815. 
  2. ^ a b c d Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (October 1997). "The capsaicin receptor: a heat-activated ion channel in the pain pathway". Nature 389 (6653): 816–24. doi:10.1038/39807. PMID 9349813. 
  3. ^ Xue Q, Yu Y, Trilk SL, Jong BE, Schumacher MA (August 2001). "The genomic organization of the gene encoding the vanilloid receptor: evidence for multiple splice variants". Genomics 76 (1-3): 14–20. doi:10.1006/geno.2001.6582. PMID 11549313. 
  4. ^ 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". Pharmacol. Rev. 57 (4): 427–50. doi:10.1124/pr.57.4.6. PMID 16382100. 
  5. ^ Everaerts W, Gees M, Alpizar YA, Farre R, Leten C, Apetrei A, Dewachter I, van Leuven F, Vennekens R, De Ridder D, Nilius B, Voets T, Talavera K (February 2011). "The capsaicin receptor TRPV1 is a crucial mediator of the noxious effects of mustard oil". Curr. Biol. 21 (4): 316–21. doi:10.1016/j.cub.2011.01.031. PMID 21315593. 
  6. ^ Cui M, Honore P, Zhong C, Gauvin D, Mikusa J, Hernandez G, Chandran P, Gomtsyan A, Brown B, Bayburt EK, Marsh K, Bianchi B, McDonald H, Niforatos W, Neelands TR, Moreland RB, Decker MW, Lee CH, Sullivan JP, Faltynek CR (2006). "TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists". J. Neurosci. 26 (37): 9385–93. doi:10.1523/JNEUROSCI.1246-06.2006. PMID 16971522. 
  7. ^ a b Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF, Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM, Di Marzo V (June 2002). "An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors". Proc. Natl. Acad. Sci. U.S.A. 99 (12): 8400–5. doi:10.1073/pnas.122196999. PMC 123079. PMID 12060783. 
  8. ^ Khairatkar-Joshi N, Szallasi A. (2009). "TRPV1 antagonists: the challenges for therapeutic targeting.". Trends in Molecular Medicine 15 (1): 14–22. doi:10.1016/j.molmed.2008.11.004. PMID 19097938. 
  9. ^ Jhaveri MD, Elmes SJ, Kendall DA, Chapman V (2005). "Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats". Eur. J. Neurosci. 22 (2): 361–70. doi:10.1111/j.1460-9568.2005.04227.x. PMID 16045489. 
  10. ^ Story GM, Crus-Orengo L (2008). "Feel the Burn". American Scientist 95 (4): 326–333. doi:10.1511/2007.66.326. ISSN 0003-0996. [dead link]
  11. ^ Gunthorpe MJ, Szallasi A (2008). "Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms". Curr. Pharm. Des. 14 (1): 32–41. doi:10.2174/138161208783330754. PMID 18220816. 
  12. ^ a b Gavva NR, Bannon AW, Surapaneni S, Hovland DN Jr, Lehto SG, Gore A, Juan T, Deng H, Han B, Klionsky L, Kuang R, Le A, Tamir R, Wang J, Youngblood B, Zhu D, Norman MH, Magal E, Treanor JJ, Louis JC (March 2007). "The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation". J. Neurosci. 27 (13): 3366–74. doi:10.1523/JNEUROSCI.4833-06.2007. PMID 17392452. 
  13. ^ Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis JC, Treanor JJ, Gavva NR, Romanovsky AA (July 2007). "Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors". J. Neurosci. 27 (28): 7459–68. doi:10.1523/JNEUROSCI.1483-07.2007. PMID 17626206. 
  14. ^ Gavva NR (2008). "Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1". Trends Pharmacol Sci. 29 (11): 550–557. doi:10.1016/j.tips.2008.08.003. PMID 18805596. 
  15. ^ Gavva NR, Treanor JJ, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, Jang GR, Kesslak JP, Ni L, Norman MH, Palluconi G, Rose MJ, Salfi M, Tan E, Romanovsky AA, Banfield C, Davar G (May 2008). "Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans". Pain 136 (1-2): 202–10. doi:10.1016/j.pain.2008.01.024. PMID 18337008. 
  16. ^ Chizh BA, O'Donnell MB, Napolitano A, Wang J, Brooke AC, Aylott MC, Bullman JN, Gray EJ, Lai RY, Williams PM, Appleby JM (November 2007). "The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans". Pain 132 (1-2): 132–41. doi:10.1016/j.pain.2007.06.006. PMID 17659837. 
  17. ^ Pareek TK, Keller J, Kesavapany S, Agarwal N, Kuner R, Pant HC, Iadarola MJ, Brady RO, Kulkarni AB (January 2007). "Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1". Proc. Natl. Acad. Sci. U.S.A. 104 (2): 660–5. doi:10.1073/pnas.0609916104. PMC 1752192. PMID 17194758. 
  18. ^ Knotkova H, Pappagallo M, Szallasi A. (2008). "Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival?". Clin. J. Pain 24 (2): 142–54. doi:10.1097/AJP.0b013e318158ed9e. PMID 18209521. 
  19. ^ 8% Capsaicin patches. "Qutenza prescribing information". Retrieved 23 November 2011. 
  20. ^ https://www.caymanchem.com/app/template/Product.vm/catalog/10115
  21. ^ Ross RA (November 2003). "Anandamide and vanilloid TRPV1 receptors". Br. J. Pharmacol. 140 (5): 790–801. doi:10.1038/sj.bjp.0705467. PMC 1574087. PMID 14517174. 
  22. ^ Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM (September 2005). "Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system". J. Biol. Chem. 280 (36): 31405–12. doi:10.1074/jbc.M501489200. PMID 15987694. 
  23. ^ Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V (September 2006). "Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma". J. Pharmacol. Exp. Ther. 318 (3): 1375–87. doi:10.1124/jpet.106.105247. PMID 16728591. 
  24. ^ Di Marzo V, Starowicz K, Cristino L (2008). "TRPV1 receptors in the central nervous system: potential for previously unforeseen therapeutic applications". Curr. Pharm. Des. 14 (1): 42–54. doi:10.2174/138161208783330790. PMID 18220817. 
  25. ^ a b Gibson HE, Edwards JG, Page RS, Van Hook MJ, Kauer JA (2008). "TRPV1 Channels Mediate Long-Term Depression at Synapses on Hippocampal Interneurons". Neuron 57 (5): 746–59. doi:10.1016/j.neuron.2007.12.027. PMC 2698707. PMID 18341994. 
  26. ^ Peters JH, McDougall SJ, Fawley JA, Smith SM, Andresen MC (2010). "Primary Afferent Activation of Thermosensitive TRPV1 Triggers Asynchronous Glutamate Release at Central Neurons". Neuron 65 (5): 657–669. doi:10.1016/j.neuron.2010.02.017. PMC 2837850. PMID 20223201. 
  27. ^ Jara-Oseguera A, Simon SA, Rosenbaum T (2008). "TRPV1: on the road to pain relief". Curr Mol Pharmacol 1 (3): 255–69. PMC 2802457. PMID 20021438. 
  28. ^ a b c d Arenkiel BR, Klein ME, Davison IG, Katz LC, Ehlers MD (2008). "Genetic control of neuronal activity in mice conditionally expressing TRPV1". Nat. Methods 5 (4): 299–302. doi:10.1038/nmeth.1190. PMC 3127246. PMID 18327266. 
  29. ^ Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M (2003). "Structural determinant of TRPV1 desensitization interacts with calmodulin". Proc. Natl. Acad. Sci. U.S.A. 100 (13): 8002–6. doi:10.1073/pnas.1337252100. PMC 164702. PMID 12808128. 
  30. ^ a b Morenilla-Palao C, Planells-Cases R, García-Sanz N, Ferrer-Montiel A (2004). "Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity". J. Biol. Chem. 279 (24): 25665–72. doi:10.1074/jbc.M311515200. PMID 15066994. 
  31. ^ Heyman I, Rang HP (May 1985). "Depolarizing responses to capsaicin in a subpopulation of rat dorsal root ganglion cells". Neurosci. Lett. 56 (1): 69–75. doi:10.1016/0304-3940(85)90442-2. PMID 4011050. 

Further reading[edit]

External links[edit]