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Trpv1

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Trpv1

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, phosphorus = orange).[1]
Identifiers
Symbols  ; DKFZp434K0220; VR1
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
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RefSeq (protein)
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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).

Contents

  • Function 1
    • Sensitization 1.1
    • Desensitization 1.2
  • Clinical significance 2
    • Peripheral nervous system 2.1
    • Antagonists 2.2
    • Agonists 2.3
      • Fatty acid metabolites 2.3.1
      • Fatty acid conjugates 2.3.2
    • Central nervous system 2.4
  • Protein engineering 3
  • Interactions 4
  • Discovery 5
  • See also 6
  • References 7
  • Further reading 8
  • External links 9

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 43 °C (109 °F); acidic conditions; capsaicin, the irritating compound in hot chili 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

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

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

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

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

Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, upon prolonged application, cause TRPV1 activity to 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 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[20] or a more physiological concentration of 10 nanomoles/liter[21] 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,[20] these linoleate metabolites have been proposed to act through TRPV1 in mediating pain perception in rodents[21][22][23] and to cause injury to airway epithelial cells and thereby to contribute to asthma disease [24] in mice and therefore possibly humans. Certain arachidonic acid metabolites, including 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid (20-HETE)[25] and 12(S)-hydroperoxy-5Z,8Z,10E,12S,14Z-eicosatetraenoic acid (12(S)-HpETE), 12(S)-hydroxy-5Z,8Z,10E,12S,14Z-eicosatetraenoic acid (12(S)-HETE (see 12-HETE), hepoxilin A3, and hepoxilin B3 likewise activate TRPV1 and may contributeto to pain perception.[26]

Fatty acid conjugates

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.[27]

Another endocannabinoid anandamide has also been shown to act on TRPV1 receptors.[28]

AM404—an active metabolite of paracetamol—that serves as an anandamide reuptake inhibitor and COX inhibitor also serves as a potent TRPV1 agonist.[29]

The plant-biosynthesized cannabinoid cannabidiol also shows "either direct or indirect activation" of TRPV1 receptors.[30]

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.[31] Furthermore, TRPV1 appears to mediate long-term depression (LTD) in the hippocampus.[32] 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.[32] 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.[33] 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

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.[34] 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.[35] 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.[35] 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.[35]

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.[35]

Interactions

TRPV1 has been shown to interact with:

Discovery

The dorsal root ganglion (DRG) neurons of mammals were known to express a heat-sensitive ion channel that could be activated by capsaicin.[38] 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

References

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  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.  
  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.  
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  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.  
  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.  
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  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.  
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  19. ^ 8% Capsaicin patches. "Qutenza prescribing information" (PDF). Retrieved 23 November 2011. 
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  27. ^ https://www.caymanchem.com/app/template/Product.vm/catalog/10115
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Further reading

  • Premkumar LS, Ahern GP (December 2000). "Induction of vanilloid receptor channel activity by protein kinase C". Nature 408 (6815): 985–90.  
  • Immke DC, Gavva NR (October 2006). "The TRPV1 receptor and nociception". Semin. Cell Dev. Biol. 17 (5): 582–91.  
  • Heiner I, Eisfeld J, Lückhoff A (2004). "Role and regulation of TRP channels in neutrophil granulocytes". Cell Calcium 33 (5-6): 533–40.  
  • 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.  
  • Clapham DE, Julius D, Montell C, Schultz G (2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacol. Rev. 57 (4): 427–50.  
  • Szallasi A, Cruz F, Geppetti P (2006). "TRPV1: a therapeutic target for novel analgesic drugs?". Trends Mol Med 12 (11): 545–54.  
  • Pingle SC, Matta JA, Ahern GP (2007). "Capsaicin receptor: TRPV1 a promiscuous TRP channel". Handb Exp Pharmacol 179 (179): 155–71.  
  • Liddle RA (2007). "The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis". Biochim. Biophys. Acta 1772 (8): 869–78.  

External links

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