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Wikipedia

TRPV1

January 26, 2023

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.[5][6] This protein is a member of the TRPV group of transient receptor potential family of ion channels.[7]

TRPV1
Identifiers
AliasesTRPV1, VR1, transient receptor potential cation channel subfamily V member 1
External IDsOMIM: 602076 MGI: 1341787 HomoloGene: 12920 GeneCards: TRPV1
Orthologs
SpeciesHumanMouse
Entrez

7442

193034

Ensembl

ENSG00000196689

ENSMUSG00000005952

UniProt

Q8NER1

Q704Y3

RefSeq (mRNA)

NM_018727
NM_080704
NM_080705
NM_080706

NM_001001445

RefSeq (protein)

NP_061197
NP_542435
NP_542436
NP_542437

NP_001001445

Location (UCSC)Chr 17: 3.57 – 3.61 MbChr 11: 73.13 – 73.15 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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[8][9] (a chemical irritant receptor) to mediate the detection of noxious environmental stimuli.[10]

Function

TRPV1 is an element of or mechanism used by the mammalian somatosensory system.[11] It 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); and allyl isothiocyanate, the pungent compound in mustard and wasabi.[12] 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.[13][14]

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.[15] Various signaling pathways such as phosphorylation by PKA and PKC, interaction with calmodulin, dephosphorylation by calcineurin,[16] and the decrease of PIP2, have been implicated in the regulation of desensitization of TRPV1. Desensitization of TRPV1 is thought to underlie the paradoxical analgesic effect of capsaicin.

Clinical significance

Peripheral nervous system

As a result of its involvement in nociception, TRPV1 has been a target for the development of pain reducers (analgesics). Three major strategies have been used:

TRPV1 Use

The TRPV1 receptor is useful to be able to measure how an organism can sense temperature change. In the lab the receptor may be removed from mice giving them the inability to detect differences in ambient temperature. In the pharmaceutical field this allows for the blocking of heat receptors giving patients with inflammatory disorders or severe burning pains a chance to heal without the pain. The lack of the TRPV1 receptor gives a glimpse into the developing brain as heat can kill most organisms in large enough doses, so this removal process shows researchers how the inability to sense heat may be detrimental to the survivability of an organism and then translate this to human heat disorders.

TRPV1 in immune cells

TRPV1 plays an important role not only in neurones but also in immune cells. Activation of TRPV1 modulates immune response including the release of inflammatory cytokines, chemokines, and the ability to phagocytose. However, the role of TRPV1 in immune cells is not entirely understood and it is currently intensely studied. TRPV1 is not the only TRP channel expressed in immune cells. TRPA1, TRPM8 and TRPV4 are the most relevant TRP channels that are also studied in immune cells.[17]

The expression of TRPV1 was confirmed in the cells of innate immunity as well as the cells of adaptive immunity. TRPV1 can be found in monocytes, macrophages, dendritic cells, T lymphocytes, natural killer cells and neutrophiles.[18] TRPV1 is said to be potentially very important in immune cell functioning as it senses higher temperature and lower pH, which can affect the immune cell performance.[19]

TRPV1 and Adaptive Immunity

TRPV1 is an important membrane channel in T cells as it regulates the influx of calcium cations. TRPV1’s involvement is mainly in T cell receptor signalling (TCR) signalling, T cell activation and TCR-mediated influx of calcium ions,[18] but it is involved in T cell cytokine production as well.[19] Indeed, T cells with TRPV1 knockout show impaired calcium uptake after T cell activation via TCR, thus they show dysregulation in signalling pathways such as NF-κB and NFAT.[17]

TRPV1 and Innate Immunity

Regarding innate immunity, activation of TRPV1 by capsaicin has been shown to suppress the production of nitrite radical, superoxide anion and hydrogen peroxide by macrophages. Furthermore, administration of capsaicin, and subsequent activation of TRPV1, suppresses phagocytosis in dendritic cells. In a mouse model, TRPV1 affect dendritic cell maturation and function, however, further studies are needed to clarify this effect in humans. In neutrophils, the increase in cytosolic calcium cations leads to synthesis of prostaglandins. Activation of TRPV1 by capsaicin modulates neutrophil immune response due to the higher influx of calcium ions into the cell.[18]

TRPV1 is also considered a novel therapeutic agent in many inflammatory diseases. Multiple studies have proven that TRPV1 influences the outcome of several inflammatory diseases such as chronic asthma, esophageal inflammation, rheumatoid arthritis and cancer. Studies using TRPV1’s agonists and antagonists have shown that their administration indeed changes the course of inflammation. However, at this point, there is a lot of contradictive evidence about what type of response, pro-inflammatory or anti-inflammatory, TRPV1’s activation induces. Further research needs to be carried out. Meanwhile, it is important to highlight that TRPV1’s influence on inflammatory diseases is probably not limited to only immune cells as it is rather an interplay between immune cells, neurons, and other cell types (epithelial cells etc.).[19]

TRPV1 and Cancer

TRPV1 was found to be overexpressed in several types of cancers, e.g., pancreatic cancer and colon adenocarcinoma. This suggest that certain types of cancers might be more prone to cell death mediated by capsaicin-induced (and also other vanilloid-induced) cell death. Indeed, studies have shown inversed correlation of consumption of chili-based foods and all-cause mortality along with cancers. This beneficial impact of the consumption of chili-based foods was attributed to capsaicinoid content.[18]

TRPV1 activation caused by its agonist capsaicin was shown to induce G0-G1 cell arrest and apoptosis in leukemic cell lines, Adult T-Cell Leukaemia and Multiple Myeloma. Capsaicin reduces the expression of anti-apoptotic protein Bcl-2 and it also promotes activation of p53, a tumour-suppressor protein known as a major regulator of cell death. This effect of capsaicin in both cases subsequently leads to above-mentioned apoptosis.[18]

TRPV1 and Neuroinflammation

The interplay between neurons and immune cells is a well-known phenomenon, therefore it is no surprise that TRPV1 plays its role in neuroinflammation, as it is expressed both in neurons and in immune cells. Significant importance should be paid to the confirmed expression of TRPV1 in microglia and astrocytes, cells found in close proximity to neurons. The neuro-immune axis is the place of production of neuroinflammatory molecules and receptors that interplay between the two systems and ensure a complex response to external stimuli (or to the body’s own pathologies). Studying TRPV1’s involvement in neuroinflammation has a great therapeutical significance for the future.[20]

Cutaneus neurons expressing TRPV1 and dendritic cells were found to be located close to each other. Activation of TRPV1 channels in neurons is associated with subsequent production of interleukin 23 (IL-23) by dendritic cells and further production of IL-17 by T cells. These interleukins are important for host defence against pathogenic fungi (such as Candida albicans) and bacteria (such as Staphylococcus aureus), thus TRPV1’s activation can lead to better defence against these pathogens, thanks to the neuro-immune axis.[19]

TRPV1 is said to contribute to autophagy of microglia via its Ca2+-signalling, which leads to mitochondria-induced cell death. The TRPV1 channel also influences microglia-induced inflammation. Migration and chemotaxis of microglia and astrocytes seems to be affected by TRPV1’s interaction with the cytoskeleton and Ca2+-signalling. TRPV1 is therefore involved in the neuro-immune axis via its function in microglia as well.[20]

TRPV1 was shown to have protective effect in neurologic disorders such as Huntington’s disease, vascular dementia, and Parkinson’s disease. However, its precise function needs to be further explored.[20]

Ligands

Antagonists

Antagonists block TRPV1 activity, thus reducing pain. Identified antagonists include the competitive antagonist capsazepine and the non-competitive antagonist ruthenium red. These agents could be useful when applied systemically.[21] 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.[22] This provides evidence that TRPV1 is capsaicin's sole receptor [23] 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.[24]

These drugs can affect body temperature (hyperthermia) which is a challenge to therapeutic application. For example, a transient temperature gain (~1 °C for a duration of approximately 40 minutes, reverting to baseline by 40 minutes) was measured in rats with the application of TRPV1 antagonist AMG-9810.[25] 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 a mild increase in body temperature (hyperthermia), it was proposed that TRPV1 is tonically active in vivo and regulates body temperature[25] 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.[26] Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance.[27] 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.[25] In 2008, AMG-517, a highly selective TRPV1 antagonist was dropped out of clinical trials due to the causation of hyperthermia (~38.3 °C mean increase which was most intense on day 1 but was attenuated on days 2–7.[28] Another molecule, SB-705498, was also evaluated in the clinic but its effect on body temperature was not reported.[29][30] As we increase understanding of modality specific agonism of TRPV1 it seems that next generation therapeutics targeting TRPV1 have the potential to side-step hyperthermia.[31] Moreover, for at least two indications or approaches this may be a secondary issue. Where the therapeutic approach (e.g., in analgesia) is agonist-mediated desensitization then the hyperthermic effects of antagonists may not be relevant. Secondarily in applications such as TRPV1 antagonism for the treatment of severe conditions such as heart failure, then there may be an acceptable trade-off with mild hyperthermia, although no hyperthermia was observed in rodent models of heart failure treated with BCTC, SB-366791 or AMG-9810.[32][33] Post translational modification of TRPV1 protein by its phosphorylation is critical for its functionality. Reports published from NIH suggest that Cdk5-mediated phosphorylation of TRPV1 is required for its ligand-induced channel opening.[34]

Agonists

TRPV1 is activated by numerous agonists from natural sources.[35] 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.[36] Eight percent 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.[37] Currently, these treatments must be re-administered on a regular (albeit infrequent) schedule in order to maintain their analgesic effects.

Cannabinoid ligands

Cannabinoid ligands include:[38]

N-Acyl amides

N-Acyl Amides that activate cannabimimetic receptors include:[38]

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.[47] or a more physiological concentration of 10 nanomoles/liter[48] 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,[47] these linoleate metabolites have been proposed to act through TRPV1 in mediating pain perception in rodents[48][49][50] and to cause injury to airway epithelial cells and thereby to contribute to asthma disease[51] in mice and therefore possibly humans. Certain arachidonic acid metabolites, including 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid (see 20-Hydroxyeicosatetraenoic acid)[52] 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 (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).[53][54][55]

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 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[56]), has been associated with ACE inhibitor-induced cough in humans.[57][58]

Resolvin E1 (RvE1), RvD2 (see resolvins), neuroprotectin D1 (NPD1), and maresin 1 (Mar1) are metabolites of the omega 3 fatty acids, 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 astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which these SPMs operate to down-regulate TRPV1 and thereby pain perception.[59][60][61][62][63]

Fatty acid conjugates

N-Arachidonoyl dopamine, an endocannabinoid found in the human CNS, structurally similar to capsaicin, activates the TRPV1 channel with an EC50 of approximately of 50 nM.[14]

N-Oleyl-dopamine, another endogenous agonist, binds to human VR1 with an Ki of 36 Nm.[64]

Another endocannabinoid anandamide has also been shown to act on TRPV1 receptors.[65]

AM404—an active metabolite of paracetamol (also known as acetaminophen) —that serves as an anandamide reuptake inhibitor and COX inhibitor also serves as a potent TRPV1 agonist.[66]

The plant-biosynthesized cannabinoid cannabidiol also shows "either direct or indirect activation" of TRPV1 receptors.[67][40] TRPV1 colocalizes with CB1 receptors and CB2 receptors in sensory and brain neurons respectively, and other plant-cannabinoids like CBN, CBG, CBC, THCV, and CBDV are also agonists of this ion channel.[68][67] There is also evidence that non cannabinoid components of the Cannabis secondary metabolome such as myrcene activate TRPV1.[69]

Vitamin D metabolites

Vitamin D metabolites, calcifediol (25-hydroxy vitamin D or 25OHD) and calcitriol (1,25-hydroxy vitamin D or 1,25OHD), act as endogenous ligands of TRPV1.[70]

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.[71] Furthermore, TRPV1 appears to mediate long-term synaptic depression (LTD) in the hippocampus.[72] 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.[72] 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.[73] 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 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.[77] 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.[5] It was the first TRPV channel to be identified. Julius was awarded the 2021 Nobel prize in Physiology or Medicine for his discovery.

See also

References

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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): 985–990. Bibcode:2000Natur.408..985P. doi:10.1038/35050121. PMID 11140687. S2CID 4372628.
  • Immke DC, Gavva NR (October 2006). "The TRPV1 receptor and nociception". Seminars in Cell & Developmental Biology. 17 (5): 582–591. 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): 533–540. doi:10.1016/S0143-4160(03)00058-7. PMID 12765698.
  • Geppetti P, Trevisani M (April 2004). "Activation and sensitisation of the vanilloid receptor: role in gastrointestinal inflammation and function". British Journal of Pharmacology. 141 (8): 1313–1320. doi:10.1038/sj.bjp.0705768. PMC 1574908. PMID 15051629.
  • Szallasi A, Cruz F, Geppetti P (November 2006). "TRPV1: a therapeutic target for novel analgesic drugs?". Trends in Molecular Medicine. 12 (11): 545–554. doi:10.1016/j.molmed.2006.09.001. PMID 16996800.
  • Pingle SC, Matta JA, Ahern GP (2007). "Capsaicin receptor: TRPV1 a promiscuous TRP channel". Transient Receptor Potential (TRP) Channels. Handb Exp Pharmacol. Handbook of Experimental Pharmacology. Vol. 179. pp. 155–71. doi:10.1007/978-3-540-34891-7_9. ISBN 978-3-540-34889-4. PMID 17217056.
  • Liddle RA (August 2007). "The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1772 (8): 869–878. doi:10.1016/j.bbadis.2007.02.012. PMC 1995747. PMID 17428642.

External links

  • Vanilloid+receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
  • Overview of all the structural information available in the PDB for UniProt: O35433 (Rat Transient receptor potential cation channel subfamily V member 1) at the PDBe-KB.
  • The Endocannabinoidome The World of Endocannabinoids and Related Mediators Book • 2014

January 26, 2023
trpv1, transient, receptor, potential, cation, channel, subfamily, member, trpv1, also, known, capsaicin, receptor, vanilloid, receptor, protein, that, humans, encoded, gene, first, isolated, member, transient, receptor, potential, vanilloid, receptor, protein. 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 5 6 This protein is a member of the TRPV group of transient receptor potential family of ion channels 7 TRPV1IdentifiersAliasesTRPV1 VR1 transient receptor potential cation channel subfamily V member 1External IDsOMIM 602076 MGI 1341787 HomoloGene 12920 GeneCards TRPV1Gene location Human Chr Chromosome 17 human 1 Band17p13 2Start3 565 444 bp 1 End3 609 411 bp 1 Gene location Mouse Chr Chromosome 11 mouse 2 Band11 B4 11 45 25 cMStart73 125 118 bp 2 End73 152 068 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inright lobe of liversural nervecerebellar hemisphereright uterine tubecanal of the cervixgastrocnemius musclegastric mucosainferior olivary nucleusvaginabody of pancreasTop expressed intrigeminal ganglionmorulaspermatocytewhite adipose tissueesophaguslipmeningesblastocystdigastric muscleneural tubeMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionnucleotide binding ion channel activity phosphoprotein binding ATP binding cation transmembrane transporter activity cation channel activity ligand gated ion channel activity calcium release channel activity temperature gated ion channel activity identical protein binding chloride channel regulator activity transmembrane signaling receptor activity excitatory extracellular ligand gated ion channel activity calcium channel activity extracellular ligand gated ion channel activity phosphatidylinositol binding metal ion binding calmodulin binding protein bindingCellular componentintegral component of membrane postsynaptic membrane cell projection membrane plasma membrane synapse cell junction dendritic spine membrane cytosol neuronal cell body intrinsic component of plasma membrane dendrite external side of plasma membrane neuron projection integral component of plasma membrane mitochondrionBiological procession transport chemosensory behavior cell surface receptor signaling pathway calcium ion transmembrane transport thermoception calcium ion transport inflammatory response transmembrane transport release of sequestered calcium ion into cytosol negative regulation of transcription by RNA polymerase II diet induced thermogenesis detection of chemical stimulus involved in sensory perception of pain microglial cell activation cellular response to growth factor stimulus positive regulation of gastric acid secretion response to peptide hormone cellular response to nerve growth factor stimulus positive regulation of nitric oxide biosynthetic process negative regulation of establishment of blood brain barrier lipid metabolism temperature homeostasis response to heat cellular response to temperature stimulus positive regulation of cytosolic calcium ion concentration peptide secretion detection of temperature stimulus involved in sensory perception of pain sensory perception of mechanical stimulus smooth muscle contraction involved in micturition behavioral response to pain response to pain cellular response to alkaloid cellular response to cytokine stimulus fever generation detection of temperature stimulus involved in thermoception positive regulation of apoptotic process urinary bladder smooth muscle contraction glutamate secretion sensory perception of pain cellular response to tumor necrosis factor cellular response to ATP ion transmembrane transport response to pH response to organonitrogen compound cellular response to heat protein homotetramerization excitatory postsynaptic potential cellular response to acidic pH response to capsazepine calcium ion import across plasma membrane negative regulation of systemic arterial blood pressure negative regulation of heart rate negative regulation of mitochondrial membrane potentialSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez7442193034EnsemblENSG00000196689ENSMUSG00000005952UniProtQ8NER1Q704Y3RefSeq mRNA NM 018727NM 080704NM 080705NM 080706NM 001001445RefSeq protein NP 061197NP 542435NP 542436NP 542437NP 001001445Location UCSC Chr 17 3 57 3 61 MbChr 11 73 13 73 15 MbPubMed search 3 4 WikidataView Edit HumanView Edit MouseThe 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 8 9 a chemical irritant receptor to mediate the detection of noxious environmental stimuli 10 Contents 1 Function 1 1 Sensitization 1 2 Desensitization 2 Clinical significance 2 1 Peripheral nervous system 2 2 TRPV1 Use 2 3 TRPV1 in immune cells 2 3 1 TRPV1 and Adaptive Immunity 2 3 2 TRPV1 and Innate Immunity 2 4 TRPV1 and Cancer 2 5 TRPV1 and Neuroinflammation 3 Ligands 3 1 Antagonists 3 2 Agonists 3 2 1 Cannabinoid ligands 3 2 2 N Acyl amides 3 2 3 Fatty acid metabolites 3 2 4 Fatty acid conjugates 3 2 5 Vitamin D metabolites 3 3 Central nervous system 4 Interactions 5 Discovery 6 See also 7 References 8 Further reading 9 External linksFunction EditTRPV1 is an element of or mechanism used by the mammalian somatosensory system 11 It 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 and allyl isothiocyanate the pungent compound in mustard and wasabi 12 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 13 14 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 disinhibition 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 15 Various signaling pathways such as phosphorylation by PKA and PKC interaction with calmodulin dephosphorylation by calcineurin 16 and the decrease of PIP2 have been implicated in the regulation of desensitization of TRPV1 Desensitization of TRPV1 is thought to underlie the paradoxical analgesic effect of capsaicin Clinical significance EditPeripheral nervous system Edit As a result of its involvement in nociception TRPV1 has been a target for the development of pain reducers analgesics Three major strategies have been used TRPV1 Use Edit The TRPV1 receptor is useful to be able to measure how an organism can sense temperature change In the lab the receptor may be removed from mice giving them the inability to detect differences in ambient temperature In the pharmaceutical field this allows for the blocking of heat receptors giving patients with inflammatory disorders or severe burning pains a chance to heal without the pain The lack of the TRPV1 receptor gives a glimpse into the developing brain as heat can kill most organisms in large enough doses so this removal process shows researchers how the inability to sense heat may be detrimental to the survivability of an organism and then translate this to human heat disorders TRPV1 in immune cells Edit TRPV1 plays an important role not only in neurones but also in immune cells Activation of TRPV1 modulates immune response including the release of inflammatory cytokines chemokines and the ability to phagocytose However the role of TRPV1 in immune cells is not entirely understood and it is currently intensely studied TRPV1 is not the only TRP channel expressed in immune cells TRPA1 TRPM8 and TRPV4 are the most relevant TRP channels that are also studied in immune cells 17 The expression of TRPV1 was confirmed in the cells of innate immunity as well as the cells of adaptive immunity TRPV1 can be found in monocytes macrophages dendritic cells T lymphocytes natural killer cells and neutrophiles 18 TRPV1 is said to be potentially very important in immune cell functioning as it senses higher temperature and lower pH which can affect the immune cell performance 19 TRPV1 and Adaptive Immunity Edit TRPV1 is an important membrane channel in T cells as it regulates the influx of calcium cations TRPV1 s involvement is mainly in T cell receptor signalling TCR signalling T cell activation and TCR mediated influx of calcium ions 18 but it is involved in T cell cytokine production as well 19 Indeed T cells with TRPV1 knockout show impaired calcium uptake after T cell activation via TCR thus they show dysregulation in signalling pathways such as NF kB and NFAT 17 TRPV1 and Innate Immunity Edit Regarding innate immunity activation of TRPV1 by capsaicin has been shown to suppress the production of nitrite radical superoxide anion and hydrogen peroxide by macrophages Furthermore administration of capsaicin and subsequent activation of TRPV1 suppresses phagocytosis in dendritic cells In a mouse model TRPV1 affect dendritic cell maturation and function however further studies are needed to clarify this effect in humans In neutrophils the increase in cytosolic calcium cations leads to synthesis of prostaglandins Activation of TRPV1 by capsaicin modulates neutrophil immune response due to the higher influx of calcium ions into the cell 18 TRPV1 is also considered a novel therapeutic agent in many inflammatory diseases Multiple studies have proven that TRPV1 influences the outcome of several inflammatory diseases such as chronic asthma esophageal inflammation rheumatoid arthritis and cancer Studies using TRPV1 s agonists and antagonists have shown that their administration indeed changes the course of inflammation However at this point there is a lot of contradictive evidence about what type of response pro inflammatory or anti inflammatory TRPV1 s activation induces Further research needs to be carried out Meanwhile it is important to highlight that TRPV1 s influence on inflammatory diseases is probably not limited to only immune cells as it is rather an interplay between immune cells neurons and other cell types epithelial cells etc 19 TRPV1 and Cancer Edit TRPV1 was found to be overexpressed in several types of cancers e g pancreatic cancer and colon adenocarcinoma This suggest that certain types of cancers might be more prone to cell death mediated by capsaicin induced and also other vanilloid induced cell death Indeed studies have shown inversed correlation of consumption of chili based foods and all cause mortality along with cancers This beneficial impact of the consumption of chili based foods was attributed to capsaicinoid content 18 TRPV1 activation caused by its agonist capsaicin was shown to induce G0 G1 cell arrest and apoptosis in leukemic cell lines Adult T Cell Leukaemia and Multiple Myeloma Capsaicin reduces the expression of anti apoptotic protein Bcl 2 and it also promotes activation of p53 a tumour suppressor protein known as a major regulator of cell death This effect of capsaicin in both cases subsequently leads to above mentioned apoptosis 18 TRPV1 and Neuroinflammation Edit The interplay between neurons and immune cells is a well known phenomenon therefore it is no surprise that TRPV1 plays its role in neuroinflammation as it is expressed both in neurons and in immune cells Significant importance should be paid to the confirmed expression of TRPV1 in microglia and astrocytes cells found in close proximity to neurons The neuro immune axis is the place of production of neuroinflammatory molecules and receptors that interplay between the two systems and ensure a complex response to external stimuli or to the body s own pathologies Studying TRPV1 s involvement in neuroinflammation has a great therapeutical significance for the future 20 Cutaneus neurons expressing TRPV1 and dendritic cells were found to be located close to each other Activation of TRPV1 channels in neurons is associated with subsequent production of interleukin 23 IL 23 by dendritic cells and further production of IL 17 by T cells These interleukins are important for host defence against pathogenic fungi such as Candida albicans and bacteria such as Staphylococcus aureus thus TRPV1 s activation can lead to better defence against these pathogens thanks to the neuro immune axis 19 TRPV1 is said to contribute to autophagy of microglia via its Ca2 signalling which leads to mitochondria induced cell death The TRPV1 channel also influences microglia induced inflammation Migration and chemotaxis of microglia and astrocytes seems to be affected by TRPV1 s interaction with the cytoskeleton and Ca2 signalling TRPV1 is therefore involved in the neuro immune axis via its function in microglia as well 20 TRPV1 was shown to have protective effect in neurologic disorders such as Huntington s disease vascular dementia and Parkinson s disease However its precise function needs to be further explored 20 Ligands EditAntagonists Edit Antagonists block TRPV1 activity thus reducing pain Identified antagonists include the competitive antagonist capsazepine and the non competitive antagonist ruthenium red These agents could be useful when applied systemically 21 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 22 This provides evidence that TRPV1 is capsaicin s sole receptor 23 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 24 These drugs can affect body temperature hyperthermia which is a challenge to therapeutic application For example a transient temperature gain 1 C for a duration of approximately 40 minutes reverting to baseline by 40 minutes was measured in rats with the application of TRPV1 antagonist AMG 9810 25 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 a mild increase in body temperature hyperthermia it was proposed that TRPV1 is tonically active in vivo and regulates body temperature 25 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 26 Recently it was proposed that predominant function of TRPV1 is body temperature maintenance 27 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 25 In 2008 AMG 517 a highly selective TRPV1 antagonist was dropped out of clinical trials due to the causation of hyperthermia 38 3 C mean increase which was most intense on day 1 but was attenuated on days 2 7 28 Another molecule SB 705498 was also evaluated in the clinic but its effect on body temperature was not reported 29 30 As we increase understanding of modality specific agonism of TRPV1 it seems that next generation therapeutics targeting TRPV1 have the potential to side step hyperthermia 31 Moreover for at least two indications or approaches this may be a secondary issue Where the therapeutic approach e g in analgesia is agonist mediated desensitization then the hyperthermic effects of antagonists may not be relevant Secondarily in applications such as TRPV1 antagonism for the treatment of severe conditions such as heart failure then there may be an acceptable trade off with mild hyperthermia although no hyperthermia was observed in rodent models of heart failure treated with BCTC SB 366791 or AMG 9810 32 33 Post translational modification of TRPV1 protein by its phosphorylation is critical for its functionality Reports published from NIH suggest that Cdk5 mediated phosphorylation of TRPV1 is required for its ligand induced channel opening 34 Agonists Edit TRPV1 is activated by numerous agonists from natural sources 35 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 36 Eight percent 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 37 Currently these treatments must be re administered on a regular albeit infrequent schedule in order to maintain their analgesic effects Cannabinoid ligands Edit Cannabinoid ligands include 38 Cannabidiol CBD agonist 39 Cannabigerol CBG agonist 40 Tetrahydrocannabivarin THCV agonist 41 Cannabigerovarin CBGV agonist 41 N Acyl amides Edit N Acyl Amides that activate cannabimimetic receptors include 38 Anandamide AEA 42 N Arachidonoyl dopamine 43 N Oleoyl dopamine 44 N Arachidonoyl taurine 45 N Docosahexaenoyl ethanolamine 46 N Docosahexaenoyl GABA 46 N Docosahexaenoyl aspartic acid 46 N Docosahexaenoyl glycine 46 N Docosahexaenoyl serine 46 N Arachidonoyl GABA 46 N Linoleyl GABA 46 Fatty acid metabolites Edit 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 47 or a more physiological concentration of 10 nanomoles liter 48 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 47 these linoleate metabolites have been proposed to act through TRPV1 in mediating pain perception in rodents 48 49 50 and to cause injury to airway epithelial cells and thereby to contribute to asthma disease 51 in mice and therefore possibly humans Certain arachidonic acid metabolites including 20 hydroxy 5Z 8Z 11Z 14Z eicosatetraenoic acid see 20 Hydroxyeicosatetraenoic acid 52 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 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 53 54 55 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 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 56 has been associated with ACE inhibitor induced cough in humans 57 58 Resolvin E1 RvE1 RvD2 see resolvins neuroprotectin D1 NPD1 and maresin 1 Mar1 are metabolites of the omega 3 fatty acids 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 astrocytes CMKLR1 GPR32 FPR2 and NMDA receptors have been proposed to be the receptors through which these SPMs operate to down regulate TRPV1 and thereby pain perception 59 60 61 62 63 Fatty acid conjugates Edit N Arachidonoyl dopamine an endocannabinoid found in the human CNS structurally similar to capsaicin activates the TRPV1 channel with an EC50 of approximately of 50 nM 14 N Oleyl dopamine another endogenous agonist binds to human VR1 with an Ki of 36 Nm 64 Another endocannabinoid anandamide has also been shown to act on TRPV1 receptors 65 AM404 an active metabolite of paracetamol also known as acetaminophen that serves as an anandamide reuptake inhibitor and COX inhibitor also serves as a potent TRPV1 agonist 66 The plant biosynthesized cannabinoid cannabidiol also shows either direct or indirect activation of TRPV1 receptors 67 40 TRPV1 colocalizes with CB1 receptors and CB2 receptors in sensory and brain neurons respectively and other plant cannabinoids like CBN CBG CBC THCV and CBDV are also agonists of this ion channel 68 67 There is also evidence that non cannabinoid components of the Cannabis secondary metabolome such as myrcene activate TRPV1 69 Vitamin D metabolites Edit Vitamin D metabolites calcifediol 25 hydroxy vitamin D or 25OHD and calcitriol 1 25 hydroxy vitamin D or 1 25OHD act as endogenous ligands of TRPV1 70 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 71 Furthermore TRPV1 appears to mediate long term synaptic depression LTD in the hippocampus 72 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 72 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 73 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 EditTRPV1 has been shown to interact with CALM1 74 SNAPAP 75 and SYT9 75 CBD 76 AEA 76 NPR1 33 PKG 33 Discovery EditThe dorsal root ganglion DRG neurons of mammals were known to express a heat sensitive ion channel that could be activated by capsaicin 77 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 5 It was the first TRPV channel to be identified Julius was awarded the 2021 Nobel prize in Physiology or Medicine for his discovery See also EditCapsaicin Capsinoids Vanilloids Vanillotoxin Cannabinoid receptor Discovery and development of TRPV1 antagonists Ruthenium red Thermoreceptor Category Somatosensory system Endocannabinoid systemReferences Edit a b 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Biological Chemistry 279 24 25665 25672 doi 10 1074 jbc M311515200 PMID 15066994 a b Fonseca BM Correia da Silva G Teixeira NA May 2018 Cannabinoid induced cell death in endometrial cancer cells involvement of TRPV1 receptors in apoptosis Journal of Physiology and Biochemistry 74 2 261 272 doi 10 1007 s13105 018 0611 7 PMID 29441458 S2CID 25294779 Heyman I Rang HP May 1985 Depolarizing responses to capsaicin in a subpopulation of rat dorsal root ganglion cells Neuroscience Letters 56 1 69 75 doi 10 1016 0304 3940 85 90442 2 PMID 4011050 S2CID 42235338 Further reading EditPremkumar LS Ahern GP December 2000 Induction of vanilloid receptor channel activity by protein kinase C Nature 408 6815 985 990 Bibcode 2000Natur 408 985P doi 10 1038 35050121 PMID 11140687 S2CID 4372628 Immke DC Gavva NR October 2006 The TRPV1 receptor and nociception Seminars in Cell amp Developmental Biology 17 5 582 591 doi 10 1016 j semcdb 2006 09 004 PMID 17196854 Heiner I Eisfeld J Luckhoff A 2004 Role and regulation of TRP channels in neutrophil granulocytes Cell Calcium 33 5 6 533 540 doi 10 1016 S0143 4160 03 00058 7 PMID 12765698 Geppetti P Trevisani M April 2004 Activation and sensitisation of the vanilloid receptor role in gastrointestinal inflammation and function British Journal of Pharmacology 141 8 1313 1320 doi 10 1038 sj bjp 0705768 PMC 1574908 PMID 15051629 Szallasi A Cruz F Geppetti P November 2006 TRPV1 a therapeutic target for novel analgesic drugs Trends in Molecular Medicine 12 11 545 554 doi 10 1016 j molmed 2006 09 001 PMID 16996800 Pingle SC Matta JA Ahern GP 2007 Capsaicin receptor TRPV1 a promiscuous TRP channel Transient Receptor Potential TRP Channels Handb Exp Pharmacol Handbook of Experimental Pharmacology Vol 179 pp 155 71 doi 10 1007 978 3 540 34891 7 9 ISBN 978 3 540 34889 4 PMID 17217056 Liddle RA August 2007 The role of Transient Receptor Potential Vanilloid 1 TRPV1 channels in pancreatitis Biochimica et Biophysica Acta BBA Molecular Basis of Disease 1772 8 869 878 doi 10 1016 j bbadis 2007 02 012 PMC 1995747 PMID 17428642 External links EditVanilloid receptors at the US National Library of Medicine Medical Subject Headings MeSH Overview of all the structural information available in the PDB for UniProt O35433 Rat Transient receptor potential cation channel subfamily V member 1 at the PDBe KB The Endocannabinoidome The World of Endocannabinoids and Related Mediators Book 2014 Retrieved from https en wikipedia org w index php title TRPV1 amp oldid 1113110324, wikipedia, wiki, book, books, library,

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