TRPV1: Wikis


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transient receptor potential cation channel, subfamily V, member 1

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]
Symbols TRPV1; DKFZp434K0220; VR1
External IDs OMIM602076 MGI1341787 HomoloGene12920 IUPHAR: TRPV1 GeneCards: TRPV1 Gene
RNA expression pattern
PBB GE TRPV1 219632 s at tn.png
More reference expression data
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 is a protein which in humans is encoded by the TRPV1 gene.[2][3] This protein is a member of the TRPV group of transient receptor potential family of ion channels.[4]



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 heat greater than 43°C and capsaicin, the pungent compound in hot chili peppers. The activation of TRPV1 leads to painful, burning sensation. Its endogenous activators include: low pH (acidic conditions), the endocannabinoid anandamide, 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. .[5][6]


The sensitivity of TRPV1 to noxious stimuli, such as high temperatures or low pH 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 TRPV1 to noxious stimuli. This manifest as an increased sensitivity to painful stimuly hyperalgesia or pain sensation in response ot non-painful stimuli allodynia. Most sensitizing pro-inflammatory agents activate the phospholipase C pathway. Phopshorylation of TRPV1 by protein kinase C have been shown to play a role in sensitzation of TRPV1.


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

Clinical significance

Peripheral nervous system

Pain is unmet medical need costing billions of dollars every year. Since 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 block TRPV1 activity, thus reducing pain, these agents could be useful when applied systemically[7]. 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.[8] This provides evidence that TRPV1 is the capsaicin's sole receptor.[9] In humans, drugs acting at TRPV1 receptors could potentially 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.[10]

The major roadblock for the usefulness of these drugs is their effect on body temparature (hyperthermia). The role of TRPV1 in the regulation of body temperature has emerged in last few years. Based on a number of TRPV1 selective antagonists causing an increase in body temperature (hyperthermia), it was proposed that TRPV1 is tonically active in vivo and regulates body temperature[11] by telling the body to "cool itself down". Without these signals, the body overheats. Similarly, this explains the propensity of capsaicin (a TRPV1 agonist) to cause sweating (ie: 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.[12] Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance [13] 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.[11] Recently, AMG 517, a highly selective TRPV1 antagonist was dropped out of clinical trials due to the undesirable level of hyperthermia.[14] A second molecule, SB-705498 was also evaluated in the clinic but its effect on body temperature was not reported.[15] 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.[16]


Agonists, such as capsaicin or 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 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 [17]

Central nervous system

TRPV1 is also expressed at high levels in the central nervous system and has been proposed as a target for treatment of not only pain but also for other conditions such as anxiety.[18] Furthermore TRPV1 appears to mediate long term depression (LTD) in the hippocampus.[19] 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 prunning of dampened down synapses is important in memory formation. In rat brain slices, activation of TRV1 with heat or capsaicin induced LTD while capsazepine blocked capsaicin's ability to induce LTD.[19] Hence there may be therapeutic potential in antagonizing 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).

See also


TRPV1 has been shown to interact with Calmodulin 1,[20] SYT9[21] and SNAPAP.[21]


  1. ^ Brauchi S, Orta G, Mascayano C, Salazar M, Raddatz N, Urbina H, Rosenmann E, Gonzalez-Nilo F, Latorre R (June 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. PMID 17548815. 
  2. ^ 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. ^ 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. 
  6. ^ 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 (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. PMID 12060783. 
  7. ^ Khairatkar-Joshi N, Szallasi A. (2009). "TRPV1 antagonists: the challenges for therapeutic targeting.". Trends in Molecular Medicine 15 (1): 14–22. PMID 19097938. 
  8. ^ 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. 
  9. ^ Story GM, Crus-Orengo L (2008). "Feel the Burn". American Scientist 95 (4): 326–333. ISSN 0003-0996. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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/ 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ 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. PMID 17194758. 
  17. ^ Knotkova H, Pappagallo M, Szallasi A. (2008). "Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival?". Clin. J. pain 24: 142–54. PMID 18209521. 
  18. ^ 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. 
  19. ^ 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. PMID 18341994. 
  20. ^ Numazaki, Mitsuko; Tominaga Tomoko, Takeuchi Kumiko, Murayama Namie, Toyooka Hidenori, Tominaga Makoto (Jun. 2003). "Structural determinant of TRPV1 desensitization interacts with calmodulin". Proc. Natl. Acad. Sci. U.S.A. (United States) 100 (13): 8002–6. doi:10.1073/pnas.1337252100. ISSN 0027-8424. PMID 12808128. 
  21. ^ a b Morenilla-Palao, Cruz; Planells-Cases Rosa, García-Sanz Nuria, Ferrer-Montiel Antonio (Jun. 2004). "Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity". J. Biol. Chem. (United States) 279 (24): 25665–72. doi:10.1074/jbc.M311515200. ISSN 0021-9258. PMID 15066994. 

Further reading

  • Premkumar LS, Ahern GP (December 2000). "Induction of vanilloid receptor channel activity by protein kinase C". Nature 408 (5): 985–90. PMID 11140687. 
  • Immke DC, Gavva NR (October 2006). "The TRPV1 receptor and nociception". Semin. Cell Dev. Biol. 17 (5): 582–91. doi:10.1016/j.semcdb.2006.09.004. PMID 17196854. 
  • Heiner I, Eisfeld J, Lückhoff A (2004). "Role and regulation of TRP channels in neutrophil granulocytes.". Cell Calcium 33 (5-6): 533–40. doi:10.1016/S0143-4160(03)00058-7. PMID 12765698. 
  • Geppetti P, Trevisani M (2004). "Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function.". Br. J. Pharmacol. 141 (8): 1313–20. doi:10.1038/sj.bjp.0705768. PMID 15051629. 
  • Clapham DE, Julius D, Montell C, Schultz G (2006). "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. 
  • Szallasi A, Cruz F, Geppetti P (2007). "TRPV1: a therapeutic target for novel analgesic drugs?". Trends in molecular medicine 12 (11): 545–54. doi:10.1016/j.molmed.2006.09.001. PMID 16996800. 
  • Pingle SC, Matta JA, Ahern GP (2007). "Capsaicin receptor: TRPV1 a promiscuous TRP channel.". Handb Exp Pharmacol 179 (179): 155–71. doi:10.1007/978-3-540-34891-7_9. PMID 17217056. 
  • Liddle RA (2007). "The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis.". Biochim. Biophys. Acta 1772 (8): 869–78. doi:10.1016/j.bbadis.2007.02.012. PMID 17428642. 

External links

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