TRPV1

2018-12-26T09:40:55Z

2003:E0:CF1B:7400:D540:8F3E:8088:692B: /* Fatty acid metabolites */ Fixed typo

{{Infobox_gene}}
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.<ref name="pmid9349813">{{cite journal | vauthors = Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D | title = The capsaicin receptor: a heat-activated ion channel in the pain pathway | journal = Nature | volume = 389 | issue = 6653 | pages = 816–24 | date = October 1997 | pmid = 9349813 | doi = 10.1038/39807 }}</ref><ref name="pmid11549313">{{cite journal | vauthors = Xue Q, Yu Y, Trilk SL, Jong BE, Schumacher MA | title = The genomic organization of the gene encoding the vanilloid receptor: evidence for multiple splice variants | journal = Genomics | volume = 76 | issue = 1–3 | pages = 14–20 | date = August 2001 | pmid = 11549313 | doi = 10.1006/geno.2001.6582 }}</ref> This protein is a member of the [[TRPV]] group of [[Transient receptor potential channel|transient receptor potential]] family of [[ion channel]]s.<ref name="pmid16382100">{{cite journal | vauthors = Clapham DE, Julius D, Montell C, Schultz G | title = International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels | journal = Pharmacol. Rev. | volume = 57 | issue = 4 | pages = 427–50 | date = December 2005 | pmid = 16382100 | doi = 10.1124/pr.57.4.6 }}</ref>

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

== Function ==

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 {{convert|43|°C}}; acidic conditions; [[capsaicin]] (the irritating compound in hot chili peppers); and [[allyl isothiocyanate]], the pungent compound in mustard and wasabi.<ref name="pmid21315593">{{cite journal | vauthors = 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 | title = The capsaicin receptor TRPV1 is a crucial mediator of the noxious effects of mustard oil | journal = Curr. Biol. | volume = 21 | issue = 4 | pages = 316–21 | date = February 2011 | pmid = 21315593 | doi = 10.1016/j.cub.2011.01.031 }}</ref> 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.<ref name="pmid16971522">{{cite journal | vauthors = 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 | title = TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists | journal = J. Neurosci. | volume = 26 | issue = 37 | pages = 9385–93 | year = 2006 | pmid = 16971522 | doi = 10.1523/JNEUROSCI.1246-06.2006 }}</ref><ref name="pmid12060783">{{cite journal | vauthors = 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 | title = An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 12 | pages = 8400–5 | date = June 2002 | pmid = 12060783 | pmc = 123079 | doi = 10.1073/pnas.122196999 }}</ref>

=== Sensitization ===

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 disinhibition of TRPV1 and, as a consequence, contribute to the sensitivity of TRPV1 to noxious stimuli.

=== Desensitization ===

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|PIP<sub>2</sub>]], have been implicated in desensitization of TRPV1. Desensitization of TRPV1 is thought to underlie the paradoxical [[analgesic]] effect of capsaicin.

== Clinical significance ==

=== Peripheral nervous system ===

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 ===

[[Receptor antagonist|Antagonists]] block TRPV1 activity, thus reducing pain. Identified antagonists include the [[Receptor antagonist#Competitive|competitive]] antagonist [[capsazepine]] and the [[Receptor antagonist#Non-competitive|non-competitive]] antagonist [[ruthenium red]].<ref name="pmid9349813"/> These agents could be useful when applied systemically.<ref name="pmid19097938">{{cite journal | vauthors = Khairatkar-Joshi N, Szallasi A | title = TRPV1 antagonists: the challenges for therapeutic targeting | journal = Trends Mol Med | volume = 15 | issue = 1 | pages = 14–22 | year = 2009 | pmid = 19097938 | doi = 10.1016/j.molmed.2008.11.004 }}</ref> Numerous TRPV1 antagonists have been developed by pharmaceutical companies. TRPV1 [[Receptor antagonist|antagonists]] have shown efficacy in reducing [[nociception]] from inflammatory and [[neuropathic pain]] models in rats.<ref name="pmid16045489">{{cite journal | vauthors = Jhaveri MD, Elmes SJ, Kendall DA, Chapman V | title = Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats | journal = Eur. J. Neurosci. | volume = 22 | issue = 2 | pages = 361–70 | year = 2005 | pmid = 16045489 | doi = 10.1111/j.1460-9568.2005.04227.x }}</ref> This provides evidence that TRPV1 is [[capsaicin]]'s sole receptor.<ref name="Story_2008">{{cite journal|vauthors=Story GM, Crus-Orengo L |title=Feel the Burn |journal=American Scientist |volume=95 |issue=4 |pages=326–333 |year=2008 |pmid= |doi=10.1511/2007.66.326 |issn=0003-0996 |url=http://www.americanscientist.org/template/AssetDetail/assetid/55542 |format= |deadurl=yes |archiveurl=https://web.archive.org/web/20080119204957/http://www.americanscientist.org/template/AssetDetail/assetid/55542 |archivedate=January 19, 2008 }}</ref>
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]].<ref name="pmid18220816">{{cite journal | vauthors = Gunthorpe MJ, Szallasi A | title = Peripheral TRPV1 receptors as targets for drug development: new molecules and mechanisms | journal = Curr. Pharm. Des. | volume = 14 | issue = 1 | pages = 32–41 | year = 2008 | pmid = 18220816 | doi = 10.2174/138161208783330754 | url = http://openurl.ingenta.com/content/nlm?genre=article&issn=1381-6128&volume=14&issue=1&spage=32&aulast=Gunthorpe }}</ref>

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 [[receptor antagonist|antagonist]]s' causing an increase in body temperature ([[hyperthermia]]), it was proposed that TRPV1 is tonically active in vivo and regulates body temperature<ref name="pmid17392452">{{cite journal | vauthors = Gavva NR, Bannon AW, Surapaneni S, Hovland DN, 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 | title = The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation | journal = J. Neurosci. | volume = 27 | issue = 13 | pages = 3366–74 | date = March 2007 | pmid = 17392452 | doi = 10.1523/JNEUROSCI.4833-06.2007 }}</ref> 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.<ref name="pmid17626206">{{cite journal | vauthors = Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis JC, Treanor JJ, Gavva NR, Romanovsky AA | title = Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors | journal = J. Neurosci. | volume = 27 | issue = 28 | pages = 7459–68 | date = July 2007 | pmid = 17626206 | doi = 10.1523/JNEUROSCI.1483-07.2007 }}</ref> Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance <ref name="pmid18805596">{{cite journal | vauthors = Gavva NR | title = Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1 | journal = Trends Pharmacol. Sci. | volume = 29 | issue = 11 | pages = 550–7 | year = 2008 | pmid = 18805596 | doi = 10.1016/j.tips.2008.08.003 }}</ref> 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.<ref name="pmid17392452"/> Recently, AMG 517, a highly selective TRPV1 antagonist was dropped out of clinical trials due to the undesirable level of hyperthermia.<ref name="pmid18337008">{{cite journal | vauthors = 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 | title = Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans | journal = Pain | volume = 136 | issue = 1–2 | pages = 202–10 | date = May 2008 | pmid = 18337008 | doi = 10.1016/j.pain.2008.01.024 }}</ref> A second molecule, SB-705498, was also evaluated in the clinic but its effect on body temperature was not reported.<ref name="pmid17659837">{{cite journal | vauthors = Chizh BA, O'Donnell MB, Napolitano A, Wang J, Brooke AC, Aylott MC, Bullman JN, Gray EJ, Lai RY, Williams PM, Appleby JM | title = The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans | journal = Pain | volume = 132 | issue = 1–2 | pages = 132–41 | date = November 2007 | pmid = 17659837 | doi = 10.1016/j.pain.2007.06.006 }}</ref> 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.<ref name="pmid17194758">{{cite journal | vauthors = Pareek TK, Keller J, Kesavapany S, Agarwal N, Kuner R, Pant HC, Iadarola MJ, Brady RO, Kulkarni AB | title = Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 2 | pages = 660–5 | date = January 2007 | pmid = 17194758 | pmc = 1752192 | doi = 10.1073/pnas.0609916104 }}</ref>

=== Agonists ===

TRPV1 is activated by numerous agonists from natural sources.<ref>Boonen, Brett; Startek, Justyna B.; Talavera, Karel (2016-01-01). Chemical Activation of Sensory TRP Channels. Topics in Medicinal Chemistry. Springer Berlin Heidelberg. pp. 1–41. [https://link.springer.com/chapter/10.1007%2F7355_2015_98] doi:10.1007/7355_2015_98.</ref> Agonists such as [[capsaicin]] and [[resiniferatoxin]] activate TRPV1 and, upon prolonged application, cause TRPV1 activity to decrease (desensitization), leading to alleviation of pain via the subsequent decrease in the TRPV1 mediated release of inflammatory molecules following exposures to noxious stimuli. Agonists can be applied locally to the painful area in various forms, generally 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.<ref>{{cite journal | vauthors = Knotkova H, Pappagallo M, Szallasi A | title = Capsaicin (TRPV1 Agonist) therapy for pain relief: farewell or revival? | journal = Clin J Pain | volume = 24 | issue = 2 | pages = 142–54 | year = 2008 | pmid = 18209521 | doi = 10.1097/AJP.0b013e318158ed9e }}</ref> 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.<ref name="Qutenza prescribing information">{{cite web|last=8% Capsaicin patches|url=http://www.qutenza.com/_docs/qutenza_full_PI_.pdf|title=Qutenza prescribing information|accessdate=23 November 2011}}</ref> Currently, these treatments must be re-administered on a regular (albeit infrequent) schedule in order to maintain their analgesic effects.

==== Fatty acid metabolites ====
Certain metabolites of polyunsaturated fatty acids have been shown to stimulate cells in a TRPV1-dependent fashion. The metabolites of [[linoleic acid]], including 13(''S'')-hydroxy-9Z,11E-octadecadienoic acid (13(S)-HODE), 13(''R'')-hydroxy-9Z,11E-octadecadienoic acid (13(''R'')-HODE, 9(''S'')-hydroxy-10(E),12(Z)-octadecadienoic acid (9(''S'')-HODE), 9(''R'')-hydroxy-10(E),12(Z)-octadecadienoic acid (9(''R'')-HODE), and their respective keto analogs, 13-oxoODE and 9-oxoODE (see [[13-HODE]] and [[9-HODE]] sections on Direct actions), activate peripheral and central mouse pain sensing neurons. Reports disagree on the potencies of these metabolites with, for example, the most potent one, 9(''S'')-HODE, requiring at least 10 micromoles/liter.<ref name="J Pharmacol 2012">{{cite journal | vauthors = De Petrocellis L, Schiano Moriello A, Imperatore R, Cristino L, Starowicz K, Di Marzo V | title = A re-evaluation of 9-HODE activity at TRPV1 channels in comparison with anandamide: enantioselectivity and effects at other TRP channels and in sensory neurons | journal = British Journal of Pharmacology | volume = 167 | issue = 8 | pages = 1643–51 | date = December 2012 | pmid = 22861649 | doi = 10.1111/j.1476-5381.2012.02122.x | pmc=3525867}}</ref> or a more physiological concentration of 10 nanomoles/liter<ref name="ReferenceA">{{cite journal | vauthors = Patwardhan AM, Scotland PE, Akopian AN, Hargreaves KM | title = Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 44 | pages = 18820–4 | date = November 2009 | pmid = 19843694 | doi = 10.1073/pnas.0905415106 | pmc=2764734}}</ref> to activate TRPV1 in rodent neurons. The TRPV1-dependency of these metabolites' activities appears to reflect their direct interaction with TPRV1. Although relatively weak agonists of TRPV1 in comparison to anandamide,<ref name="J Pharmacol 2012"/> these linoleate metabolites have been proposed to act through TRPV1 in mediating pain perception in rodents<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Patwardhan AM, Akopian AN, Ruparel NB, Diogenes A, Weintraub ST, Uhlson C, Murphy RC, Hargreaves KM | title = Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents | journal = The Journal of Clinical Investigation | volume = 120 | issue = 5 | pages = 1617–26 | date = May 2010 | pmid = 20424317 | doi = 10.1172/JCI41678 | pmc=2860941}}</ref><ref>{{cite journal | vauthors = Sisignano M, Angioni C, Ferreiros N, Schuh CD, Suo J, Schreiber Y, Dawes JM, Antunes-Martins A, Bennett DL, McMahon SB, Geisslinger G, Scholich K | title = Synthesis of lipid mediators during UVB-induced inflammatory hyperalgesia in rats and mice | journal = PLoS One | volume = 8 | issue = 12 | pages = e81228 | pmid = 24349046 | doi = 10.1371/journal.pone.0081228 | pmc=3857181 | year=2013}}</ref> and to cause injury to airway epithelial cells and thereby to contribute to [[asthma]] disease<ref>{{cite journal | vauthors = Mabalirajan U, Rehman R, Ahmad T, Kumar S, Singh S, Leishangthem GD, Aich J, Kumar M, Khanna K, Singh VP, Dinda AK, Biswal S, Agrawal A, Ghosh B | title = Linoleic acid metabolite drives severe asthma by causing airway epithelial injury | journal = Scientific Reports | volume = 3 | pages = 1349 | pmid = 23443229 | doi = 10.1038/srep01349 | pmc=3583002 | year=2013}}</ref> in mice and therefore possibly humans. Certain [[arachidonic acid]] metabolites, including 20-hydroxy-5''Z'',8''Z'',11''Z'',14''Z''-eicosatetraenoic acid (see [[20-Hydroxyeicosatetraenoic acid]])<ref>{{cite journal | vauthors = Wen H, Östman J, Bubb KJ, Panayiotou C, Priestley JV, Baker MD, Ahluwalia A | title = 20-Hydroxyeicosatetraenoic acid (20-HETE) is a novel activator of transient receptor potential vanilloid 1 (TRPV1) channel | journal = The Journal of Biological Chemistry | volume = 287 | issue = 17 | pages = 13868–76 | date = April 2012 | pmid = 22389490 | doi = 10.1074/jbc.M111.334896 | pmc=3340178}}</ref> and 12(''S'')-hydroperoxy-5''Z'',8''Z'',10''E'',12''S'',14''Z''-eicosatetraenoic acid (12(S)-HpETE), 12(''S'')-hydroxy-5''Z'',8''Z'',10''E'',12''S'',14''Z''-eicosatetraenoic acid (12(''S'')-HETE (see [[12-HETE]]), [[hepoxilin]] A3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid) likewise activate TRPV1 and may thereby contribute to tactile hyperalgesia and allodynia (see [[Hepoxilin#Pain perception]]).<ref>{{cite journal | vauthors = Gregus AM, Doolen S, Dumlao DS, Buczynski MW, Takasusuki T, Fitzsimmons BL, Hua XY, Taylor BK, Dennis EA, Yaksh TL | title = Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 17 | pages = 6721–6 | date = April 2012 | pmid = 22493235 | doi = 10.1073/pnas.1110460109 | pmc=3340022}}</ref><ref>{{cite journal | vauthors = Gregus AM, Dumlao DS, Wei SC, Norris PC, Catella LC, Meyerstein FG, Buczynski MW, Steinauer JJ, Fitzsimmons BL, Yaksh TL, Dennis EA | title = Systematic analysis of rat 12/15-lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia | journal = FASEB Journal | volume = 27 | issue = 5 | pages = 1939–49 | date = May 2013 | pmid = 23382512 | doi = 10.1096/fj.12-217414 | pmc=3633813}}</ref><ref>{{cite journal | vauthors = Pace-Asciak CR | title = Pathophysiology of the hepoxilins | journal = Biochimica et Biophysica Acta | volume = 1851 | issue = 4 | pages = 383–96 | date = April 2015 | pmid = 25240838 | doi = 10.1016/j.bbalip.2014.09.007 }}</ref>

Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that another arachidonic acid metabolite, [[Prostaglandin E2]], operates through its [[prostaglandin EP3 receptor|prostaglandin EP3]] [[G protein coupled receptor]] to trigger [[cough]] responses. Its mechanism of action involves activation and/or sensitization of TRPV1 (as well as [[TRPA1]]) receptors, presumably by an indirect mechanism. Genetic polymorphism in the EP3 receptor (rs11209716<ref>https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=11209716&pt=1-qmUGHsLMC5BR3la78zzEFD7-YFKRZ0LTSVR2ExVBUrQRWkr2</ref>), has been associated with [[ACE inhibitor#adverse effects cough|ACE inhibitor]]-induced cough in humans.<ref name="pmid21727026">{{cite journal | vauthors = Maher SA, Dubuis ED, Belvisi MG | title = G-protein coupled receptors regulating cough | journal = Current Opinion in Pharmacology | volume = 11 | issue = 3 | pages = 248–53 | year = 2011 | pmid = 21727026 | doi = 10.1016/j.coph.2011.06.005 | url = }}</ref><ref name="pmid21052031">{{cite journal | vauthors = Grilo A, Sáez-Rosas MP, Santos-Morano J, Sánchez E, Moreno-Rey C, Real LM, Ramírez-Lorca R, Sáez ME | title = Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough | journal = Pharmacogenetics and Genomics | volume = 21 | issue = 1 | pages = 10–7 | year = 2011 | pmid = 21052031 | doi = 10.1097/FPC.0b013e328341041c | url = }}</ref>

Resolvin E1 (RvE1), RvD2 (see [[resolvin]]s), [[neuroprotectin D1]] (NPD1), and [[maresin]] 1 (Mar1) are metabolites of the [[omega 3 fatty acid]]s, [[eicosapentaenoic acid]] (for RvE1) or [[docosahexaenoic acid]] (for RvD2, NPD1, and Mar1). These metabolites are members 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. These SPMs also dampen pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effects involves the inhibition of TRPV1, probably (in at least certain cases) by an indirect effect wherein they activate other receptors located on the neurons or nearby [[microglia]] or [[astrocyte]]s. [[CMKLR1]], [[GPR32]], [[FPR2]], and [[NMDA receptor]]s have been proposed to be the receptors through which these SPMs operate to [[down-regulate]] TRPV1 and thereby pain perception.<ref name="pmid25052386">{{cite journal | vauthors = Qu Q, Xuan W, Fan GH | title = Roles of resolvins in the resolution of acute inflammation | journal = Cell Biology International | volume = 39 | issue = 1 | pages = 3–22 | year = 2015 | pmid = 25052386 | doi = 10.1002/cbin.10345 | url = }}</ref><ref name="pmid25359497">{{cite journal | vauthors = Serhan CN, Chiang N, Dalli J, Levy BD | title = Lipid mediators in the resolution of inflammation | journal = Cold Spring Harbor Perspectives in Biology | volume = 7 | issue = 2 | pages = a016311 | year = 2015 | pmid = 25359497 | pmc = 4315926 | doi = 10.1101/cshperspect.a016311 | url = }}</ref><ref name="pmid26339646">{{cite journal | vauthors = Lim JY, Park CK, Hwang SW | title = Biological Roles of Resolvins and Related Substances in the Resolution of Pain | journal = BioMed Research International | volume = 2015 | issue = | pages = 830930 | year = 2015 | pmid = 26339646 | pmc = 4538417 | doi = 10.1155/2015/830930 | url = }}</ref><ref name="pmid21963090">{{cite journal | vauthors = Ji RR, Xu ZZ, Strichartz G, Serhan CN | title = Emerging roles of resolvins in the resolution of inflammation and pain | journal = Trends in Neurosciences | volume = 34 | issue = 11 | pages = 599–609 | year = 2011 | pmid = 21963090 | pmc = 3200462 | doi = 10.1016/j.tins.2011.08.005 | url = }}</ref><ref name="pmid25857211">{{cite journal | vauthors = Serhan CN, Chiang N, Dalli J | title = The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution | journal = Seminars in Immunology | volume = 27 | issue = 3 | pages = 200–15 | year = 2015 | pmid = 25857211 | pmc = 4515371 | doi = 10.1016/j.smim.2015.03.004 | url = }}</ref>

==== Fatty acid conjugates ====

[[N-Arachidonoyl dopamine]], a endocannabinoid found in the human CNS, structurally similar to capsaicin, activates the TRPV1 channel with an [[EC50|EC<sub>50</sub>]] of approximately of 50 nM.<ref name="pmid12060783" />

N-Oleyl-dopamine, another endogenous agonist, binds bind to human VR1 with an Ki of 36 Nm.<ref>{{cite web|url=https://www.caymanchem.com/app/template/Product.vm/catalog/10115|title=N-Oleoyl Dopamine (CAS 105955-11-1)|author=|date=|website=www.caymanchem.com}}</ref>

Another [[endocannabinoid]] [[anandamide]] has also been shown to act on TRPV1 receptors.<ref name="pmid14517174">{{cite journal | vauthors = Ross RA | title = Anandamide and vanilloid TRPV1 receptors | journal = Br. J. Pharmacol. | volume = 140 | issue = 5 | pages = 790–801 | date = November 2003 | pmid = 14517174 | pmc = 1574087 | doi = 10.1038/sj.bjp.0705467 }}</ref>

[[AM404]]—an [[active metabolite]] of [[paracetamol]]—that serves as an [[anandamide]] [[reuptake inhibitor]] and [[COX]] inhibitor also serves as a potent TRPV1 agonist.<ref name="pmid15987694">{{cite journal | vauthors = Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM | title = Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system | journal = J. Biol. Chem. | volume = 280 | issue = 36 | pages = 31405–12 | date = September 2005 | pmid = 15987694 | doi = 10.1074/jbc.M501489200 }}</ref>

The plant-biosynthesized cannabinoid [[cannabidiol]] also shows "either direct or indirect activation" of TRPV1 receptors.<ref name="pmid16728591">{{cite journal | vauthors = Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V | title = Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma | journal = J. Pharmacol. Exp. Ther. | volume = 318 | issue = 3 | pages = 1375–87 | date = September 2006 | pmid = 16728591 | doi = 10.1124/jpet.106.105247 }}</ref> TRPV1 colocalizes with [[Cannabinoid receptor type 1|CB1 receptors]] and [[Cannabinoid receptor type 2|CB2 receptors]] in [[Sensory neuron|sensory]] and [[brain]] [[neuron]]s respectively, and other plant-cannabinoids like [[Cannabinol|CBN]], [[Cannabigerol|CBG]], [[Cannabichromene|CBC]], [[Tetrahydrocannabivarin|THCV]], and [[Cannabidivarin|CBDV]] are also agonists of this [[ion channel]].<ref>{{Cite journal|last=Morales|first=Paula|last2=Hurst|first2=Dow P.|last3=Reggio|first3=Patricia H.|date=2017|title=Molecular Targets of the Phytocannabinoids-A Complex Picture|journal=Progress in the chemistry of organic natural products|volume=103|pages=103–131|doi=10.1007/978-3-319-45541-9_4|issn=2191-7043|pmc=5345356|pmid=28120232}}</ref>

=== Central nervous system ===

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]].<ref name="pmid18220817">{{cite journal | vauthors = Starowicz K, Cristino L, Di Marzo V | title = TRPV1 receptors in the central nervous system: potential for previously unforeseen therapeutic applications | journal = Curr. Pharm. Des. | volume = 14 | issue = 1 | pages = 42–54 | year = 2008 | pmid = 18220817 | doi = 10.2174/138161208783330790 | url = http://openurl.ingenta.com/content/nlm?genre=article&issn=1381-6128&volume=14&issue=1&spage=42&aulast=Starowicz }}</ref>
Furthermore, TRPV1 appears to mediate long-term synaptic depression (LTD) in the [[hippocampus]].<ref name="pmid18341994">{{cite journal | vauthors = Gibson HE, Edwards JG, Page RS, Van Hook MJ, Kauer JA | title = TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons | journal = Neuron | volume = 57 | issue = 5 | pages = 746–59 | year = 2008 | pmid = 18341994 | pmc = 2698707 | doi = 10.1016/j.neuron.2007.12.027 }}</ref> 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.<ref name="pmid18341994"/> 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.<ref name="pmid20223201">{{cite journal | vauthors = Peters JH, McDougall SJ, Fawley JA, Smith SM, Andresen MC | title = Primary afferent activation of thermosensitive TRPV1 triggers asynchronous glutamate release at central neurons | journal = Neuron | volume = 65 | issue = 5 | pages = 657–69 | year = 2010 | pmid = 20223201 | pmc = 2837850 | doi = 10.1016/j.neuron.2010.02.017 }}</ref> 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).

== Interactions ==

TRPV1 has been shown to [[Protein-protein interaction|interact]] with:
* [[Calmodulin 1|CALM1]],<ref name = pmid12808128>{{cite journal | vauthors = Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M | title = Structural determinant of TRPV1 desensitization interacts with calmodulin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 13 | pages = 8002–6 | year = 2003 | pmid = 12808128 | pmc = 164702 | doi = 10.1073/pnas.1337252100 }}</ref>
* [[SNAPAP]],<ref name = pmid15066994/> and
* [[SYT9]].<ref name = pmid15066994>{{cite journal | vauthors = Morenilla-Palao C, Planells-Cases R, García-Sanz N, Ferrer-Montiel A | title = Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity | journal = J. Biol. Chem. | volume = 279 | issue = 24 | pages = 25665–72 | year = 2004 | pmid = 15066994 | doi = 10.1074/jbc.M311515200 }}</ref>
* [[Cannabidiol|CBD]]<ref name=":0">{{Cite journal|last=Fonseca|first=B. M.|last2=Correia-da-Silva|first2=G.|last3=Teixeira|first3=N. A.|date=2018-02-13|title=Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis|url=https://link.springer.com/article/10.1007/s13105-018-0611-7|journal=Journal of Physiology and Biochemistry|language=en|pages=1–12|doi=10.1007/s13105-018-0611-7|issn=1138-7548}}</ref>
* [[Anandamide|AEA]]<ref name=":0" />

== Discovery ==

The [[dorsal root ganglion]] (DRG) [[neuron]]s of mammals were known to express a heat-sensitive ion channel that could be activated by capsaicin.<ref name="pmid4011050">{{cite journal | vauthors = Heyman I, Rang HP | title = Depolarizing responses to capsaicin in a subpopulation of rat dorsal root ganglion cells | journal = Neurosci. Lett. | volume = 56 | issue = 1 | pages = 69–75 | date = May 1985 | pmid = 4011050 | doi = 10.1016/0304-3940(85)90442-2 }}</ref> 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|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.<ref name="pmid9349813"/>

== See also ==
*[[Capsaicin]]
*[[Capsinoids]]
*[[Vanilloids]]
*[[Vanillotoxin]]
*[[Cannabinoid receptor]]
*[[Discovery and development of TRPV1 antagonists]]
*[[Ruthenium red]]

== References ==
{{Reflist|2}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Premkumar LS, Ahern GP | title = Induction of vanilloid receptor channel activity by protein kinase C | journal = Nature | volume = 408 | issue = 6815 | pages = 985–90 | date = December 2000 | pmid = 11140687 | doi = 10.1038/35050121 }}
* {{cite journal | vauthors = Immke DC, Gavva NR | title = The TRPV1 receptor and nociception | journal = Semin. Cell Dev. Biol. | volume = 17 | issue = 5 | pages = 582–91 | date = October 2006 | pmid = 17196854 | doi = 10.1016/j.semcdb.2006.09.004 }}
* {{cite journal | vauthors = Heiner I, Eisfeld J, Lückhoff A | title = Role and regulation of TRP channels in neutrophil granulocytes | journal = Cell Calcium | volume = 33 | issue = 5–6 | pages = 533–40 | year = 2004 | pmid = 12765698 | doi = 10.1016/S0143-4160(03)00058-7 }}
* {{cite journal | vauthors = Geppetti P, Trevisani M | title = Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function | journal = Br. J. Pharmacol. | volume = 141 | issue = 8 | pages = 1313–20 | year = 2004 | pmid = 15051629 | pmc = 1574908 | doi = 10.1038/sj.bjp.0705768 }}
* {{cite journal | vauthors = Clapham DE, Julius D, Montell C, Schultz G | title = International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels | journal = Pharmacol. Rev. | volume = 57 | issue = 4 | pages = 427–50 | year = 2005 | pmid = 16382100 | doi = 10.1124/pr.57.4.6 }}
* {{cite journal | vauthors = Szallasi A, Cruz F, Geppetti P | title = TRPV1: a therapeutic target for novel analgesic drugs? | journal = Trends Mol Med | volume = 12 | issue = 11 | pages = 545–54 | year = 2006 | pmid = 16996800 | doi = 10.1016/j.molmed.2006.09.001 }}
* {{cite journal | vauthors = Pingle SC, Matta JA, Ahern GP | title = Capsaicin receptor: TRPV1 a promiscuous TRP channel | journal = Handb Exp Pharmacol | volume = 179 | issue = 179 | pages = 155–71 | year = 2007 | pmid = 17217056 | doi = 10.1007/978-3-540-34891-7_9 | series = Handbook of Experimental Pharmacology | isbn = 978-3-540-34889-4 }}
* {{cite journal | vauthors = Liddle RA | title = The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis | journal = Biochim. Biophys. Acta | volume = 1772 | issue = 8 | pages = 869–78 | year = 2007 | pmid = 17428642 | pmc = 1995747 | doi = 10.1016/j.bbadis.2007.02.012 }}
{{refend}}

== External links ==
*{{MeshName|Vanilloid+receptors}}

{{Ion channels|g4}}
{{Transient receptor potential channel modulators}}

[[Category:Ion channels]]

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