Alternative titles; symbols
HGNC Approved Gene Symbol: TRPV1
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38) : 17:3,565,446-3,609,411 (from NCBI)
The vanilloid compound capsaicin, the main pungent component in 'hot' chili peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. Caterina et al. (1997) used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from rat sensory neurons. The rat cDNA encodes an 838-amino acid polypeptide with a predicted relative mass of 95,000 and a hydrophobicity profile suggestive of a 6-transmembrane domain-containing receptor. Caterina et al. (1997) showed that the receptor is a nonselective cation channel that is structurally related to members of the Drosophila TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo. Because a vanilloid moiety constitutes an essential chemical component of capsaicin and resiniferatoxin structures, the proposed site of action of these compounds is generally referred to as the vanilloid receptor. Accordingly, Caterina et al. (1997) named their cloned cDNA VR1, for 'vanilloid receptor subtype-1.' An expressed sequence tag (EST) database search revealed several human clones with a high degree of similarity to VR1 at both the DNA and predicted amino acid sequence levels.
Using the rat Vr1 sequence as query, Hayes et al. (2000) identified a human fetal spleen EST containing VR1. They cloned the full-length cDNA by 5-prime RACE and RT-PCR of brain and placenta mRNA. The deduced 839-amino acid protein contains 3 ankyrin repeats, 6 transmembrane domains, and a pore loop. It also has putative sites for protein kinase A (see 176911) phosphorylation and for N-glycosylation. The human sequence shares 86% identity with the rat Vr1 protein, with reduced identity at the N and C termini. PCR analysis showed a uniformly low expression of VR1 in brain and peripheral tissues. Highest expression was found in dorsal root ganglion (DRG).
Using a fragment of the rat Vr1 cDNA as probe, Cortright et al. (2001) cloned human VR1 from a DRG cDNA library. Northern blot analysis identified a 4.2-kb transcript restricted to DRG. A faint smear in the 3 to 5 kb range was detected in kidney. Ribonuclease protection assays confirmed expression of VR1 in kidney, as well as in brain cortex and cerebellum.
Hayes et al. (2000) and Cortright et al. (2001) determined that human VR1 has physiologic characteristics similar to those of the rat protein when expressed in Xenopus oocytes or HEK293 cells. VR1 responded to capsaicin, pH, and temperature by generating inward membrane currents.
VR1 and native VRs are nonselective cation channels directly activated by harmful heat, extracellular protons, and vanilloid compounds. VR1 is also expressed in nonsensory tissue and may mediate inflammatory rather than acute thermal pain. Premkumar and Ahern (2000) showed that activation of PKC-epsilon (PRKCE; 176975) induces VR1 channel activity at room temperature in the absence of any other agonist. They also observed this effect in native VRs from sensory neurons, and phorbol esters induced a vanilloid-sensitive calcium rise in these cells. Moreover, the proinflammatory peptide bradykinin, and the putative endogenous ligand anandamide, induced and enhanced VR activity, respectively, in a PKC-dependent manner. These results suggested that PKC may link a range of stimuli to the activation of VRs.
Numazaki et al. (2002) demonstrated direct phosphorylation of the first intracellular loop and of the C terminus of VR1 by PRKCE. Mutation analysis revealed specific phosphorylation on ser502 and ser800. Bhave et al. (2002) showed that cAMP-dependent protein kinase A (PRKACA; 601639) directly phosphorylates VR1 at the cytoplasmic ser116 residue and prevents agonist-induced VR1 desensitization in vitro, as measured by current magnitude. They suggested a role for this mechanism in inflammatory hyperalgesia after tissue injury.
Chuang et al. (2001) demonstrated that bradykinin- or NGF-mediated potentiation of thermal sensitivity in vivo requires expression of VR1. Diminution of plasma membrane phosphatidylinositol-4,5,bisphosphate levels through antibody sequestration or PLC-mediated hydrolysis mimics the potentiating effects of bradykinin or NGF at the cellular level. Moreover, recruitment of PLC-gamma (172420) to TRK-alpha (191315) is essential for NGF-mediated potentiation of channel activity, and biochemical studies suggested that VR1 associates with this complex. Chuang et al. (2001) concluded that their studies delineate a biochemical mechanism through which bradykinin and NGF produce hypersensitivity and might explain how the activation of PLC signaling systems regulates other members of the TRP channel family.
Trevisani et al. (2002) noted the common observation that alcohol induces a 'burning' sensation in patients with esophagitis and skin wounds and studied the effects of ethanol on the VR1 receptor, which mediates noxious heat. Ethanol (0.1-3%) enhanced the response of VR1 to agonists, such as capsaicin, and potentiated the activation effects of protons, anandamide, and heat, as measured by calcium influx. Ethanol also reduced the temperature activation threshold of VR1 and induced tachykinin-dependent plasma extravasation via VR1 activation. These findings supported a role of VR1 receptors in visceral pain and inflammation aggravated by alcohol.
Capsaicin is more intensively 'hot' in PTC/PROP tasters (171200) than in nontasters (Bartoshuk et al., 1994). Repeated exposure to capsaicin (over the course of days) decreases the overall burn intensity (Stevenson and Prescott, 1994). This may explain why frequent consumers of chili are less sensitive to its perceived burn (Stevenson and Yeomans, 1993). Other pungent spices that are structurally related to capsaicin include piperine (from black pepper) and zingerone (from ginger). Prescott and Stevenson (1996) observed that the frequent use of chili decreased the psychophysical response to zingerone, suggesting that the 2 compounds act through a common mechanism. Experiments in rodents showed that capsaicin, zingerone, and piperine bind to different subtypes of a common receptor (Liu and Simon, 1996).
Capsaicin in chili peppers offers protection from predatory mammals. Birds are indifferent to the pain-producing effects of capsaicin and therefore serve as vectors for seed dispersal. Jordt and Julius (2002) determined the molecular basis for this species-specific behavioral response by identifying a domain of the rat vanilloid receptor that confers sensitivity to capsaicin to the normally insensitive chicken ortholog. Like its mammalian counterpart, the chicken receptor is activated by heat or protons, consistent with the fact that both mammals and birds detect noxious heat and experience thermal hypersensitivity. These findings provided a molecular basis for the ecologic phenomenon of directed deterrence and suggested that the capacity to detect capsaicin-like inflammatory substances is a recent acquisition of mammalian vanilloid receptors.
Although fecal urgency and incontinence with rectal hypersensitivity is sometimes a feature of rectal cancer and inflammatory bowel disease, it often occurs with no obvious underlying cause. Some patients are so severely affected that incontinence occurs even when the anal sphincter mechanism is intact. Chan et al. (2003) postulated that rectal hypersensitivity and subsequent fecal urgency is due to sensitization, sprouting, or phenotypic changes of nerves in transmission of visceral sensation. They compared full-thickness rectal biopsy samples from 9 patients with physiologically characterized rectal hypersensitivity and severe fecal urgency (defined as inability to inhibit defecation for more than a few seconds) with samples from 12 controls. In rectal hypersensitivity, nerve fibers immunoreactive to TRPV1 were increased in muscle, submucosal, and mucosal layers. This and other observations suggested that fecal urgency and rectal hypersensitivity could result from increased numbers of polymodal sensory nerve fibers expressing TRPV1. Although the triggering factor or factors remained uncertain, drugs that target nerve endings expressing this receptor, such as topical resiniferatoxin, were suggested as possible therapy.
Walker et al. (2003) showed that TRPV1 antagonists had antihyperalgesic activity in animal models of chronic inflammatory and neuropathic pain; however, there were significant species-specific differences in responses.
Prescott and Julius (2003) identified a site within the C-terminal domain of TRPV1 that is required for phosphatidylinositol-4,5-bisphosphate (PIP2)-mediated inhibition of channel gating. Mutations that weaken PIP2-TRPV1 interaction reduced thresholds for chemical or thermal stimuli, whereas TRPV1 channels in which this region was replaced with a lipid-binding domain from PIP2-activated potassium channels remained inhibited by PIP2. The PIP2-interaction domain therefore serves as a critical determinant of thermal threshold and dynamic sensitivity range, tuning TRPV1, and thus the sensory neuron, to appropriately detect heat under normal or pathophysiologic conditions. The critical region in the C terminal of TRPV1 spans amino acids 777 to 820.
Voets et al. (2004) demonstrated that temperature sensing is tightly linked to voltage-dependent gating in the cold-sensitive channel TRPM8 (606678) and the heat-sensitive channel TRPV1. Both channels are activated upon depolarization, and changes in temperature result in graded shifts of their voltage-dependent activation curves. The chemical agonists menthol (TRPM8) and capsaicin (TRPV1) function as gating modifiers, shifting activation curves towards physiologic membrane potentials. Kinetic analysis of gating at different temperatures indicated that temperature sensitivity in TRPM8 and TRPV1 arises from a 10-fold difference in the activation energies associated with voltage-dependent opening and closing. Voets et al. (2004) concluded that their results suggested a simple unifying principle that explains both cold and heat sensitivity in TRP channels, namely, that membrane voltage contributes to the fine-tuning of cold and heat sensitivity in sensory cells.
Raw garlic, but not cooked garlic, elicits painful burning and prickling sensations when cut and placed on the tongue or lips. Macpherson et al. (2005) showed that raw, but not baked, garlic activated TRPA1 (604775) and TRPV1 and that allicin, an unstable component of fresh garlic, is the chemical responsible for TRPA1 and TRPV1 activation.
Siemens et al. (2006) showed that venom from Psalmopoeus cambridgei, a tarantula that is native to the West Indies, contains 3 inhibitor cystine knot (ICK) peptides that target the capsaicin receptor TRPV1. In contrast with the predominant role of ICK toxins as channel inhibitors, these previously unknown 'vanillotoxins' function as TRPV1 agonists, providing new tools for understanding mechanisms of TRP channel gating. Some vanillotoxins also inhibit voltage-gated potassium channels, supporting potential similarities between TRP and voltage-gated channel structures. Siemens et al. (2006) concluded that TRP channels can be included among the targets of peptide toxins, showing that animals, like plants (i.e., chili peppers), avert predators by activating TRP channels on sensory nerve fibers to elicit pain and inflammation.
Binshtok et al. (2007) tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. They showed that charged sodium channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability. Inhibition by coapplied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 hours) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits.
Kim et al. (2008) found that heterologous expression of mouse Pirt (612068) enhanced the channel activity of TRPV1. The C terminus of Pirt bound to TRPV1 and to most phosphoinositides tested, and it was required for enhancement of TRPV1 activity by PIP2. Pirt -/- mice showed impaired responses to noxious heat and capsaicin exposure. Pirt knockout did not alter expression of Trpv1, but it attenuated Trpv1-mediated currents in isolated Pirt -/- dorsal root ganglion neurons. Kim et al. (2008) concluded that PIRT is a key component of the TRPV1 complex that positively regulates TRPV1 activity.
The Chinese bird spider, or earth tiger, is a large tarantula that inhabits deep underground burrows in tropical regions of southern China and Vietnam. Its bites cause painful, but usually nonlethal, reactions in humans. Bohlen et al. (2010) described a toxin from the earth tiger tarantula that they called the double-knot toxin (DkTx) because it consists of 2 head-to-tail inhibitor cysteine knot (ICK) units. By screening a panel of TRPs, they found that purified DkTx targeted TRPV1 channels in a virtually irreversible manner. The bivalency of DkTx was required for its persistent toxin action. Trigeminal neuron cells from mice lacking Trpv1 failed to show calcium increases when exposed to DkTx. Binding of DkTx to TRPV1, which required residues in the pore-forming region of the channel, locked the receptor in the open state.
Riol-Blanco et al. (2014) exposed the skin of mice to imiquimod, which induces IL23 (see 605580)-dependent psoriasis-like inflammation, and showed that a subset of sensory neurons expressing the ion channels TRPV1 and NAV1.8 (SCN10A; 604427) is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of dermal dendritic cells (DDCs), the principal source of IL23, is in close contact with these nociceptors. Upon selective pharmacologic or genetic ablation of nociceptors, DDCs failed to produce IL23 in imiquimod-exposed skin. Consequently, the local production of IL23-dependent inflammatory cytokines by dermal gamma-delta-T17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. Riol-Blanco et al. (2014) concluded that TRPV1-positive/NAV1.8-positive nociceptors, by interacting with DDCs, regulate the IL23/IL17 (603149) pathway and control cutaneous immune responses.
Weng et al. (2015) noted that TRPV1 interacts with TRPA1 and inhibits its activity in DRG neurons. They found that Tmem100 (616334) was expressed in Trpa1- and Trpv1-positive mouse DRG neurons and that Tmem100 interacted with both Trpa1 and Trvp1 in coimmunoprecipitation and protein pull-down assays. Tmem100 weakened the association of Trpa1 with Trpv1, thereby reducing Trpv1-mediated inhibition of Trpa1 in DRG neurons. Tmem100 also increased Trpa1 activity when coexpressed with Trpa1 and Trpv1 in CHO and HEK293T cells. Tmem100 increased the open probability of Trpa1 channels in response to chemical pain signals, but only in the presence of Trpv1. Tmem100 also increased cell surface expression of Trpa1 and Trpv1. Selective elimination of Tmem100 in mouse DRG primary sensory neurons reduced the responses of these mice to noxious chemical, mechanical, and inflammatory stimuli, but had no effect on cold-induced pain responses. Patch-clamp recordings of Tmem100-knockout DRG neurons revealed reduced capsaicin-evoked Trpa1 activity compared with controls. Weng et al. (2015) concluded that TMEM100 is an adaptor protein that regulates the association between TRPA1 and TRPV1.
Buntinx et al. (2016) noted that the most common mutation in Northern European patients with cystinosis (219800) is a 57-kb deletion in the CTNS gene (606272.0005) that extends into the noncoding region upstream of the TRPV1 start codon. They found that patients heterozygous for the deletion showed normal sensory responses, whereas patients homozygous for the mutation exhibited a 60% reduction in vasodilation and pain evoked by capsaicin, as well as an increase in heat detection threshold. Responses to cold, mechanical stimuli, or cinnamaldehyde, a TRPA1 agonist, were unaltered. Buntinx et al. (2016) concluded that cystinosis patients homozygous for the 57-kb CTNS deletion have a strong reduction of TRPV1 function, possibly accounting for sensory alterations and thermoregulatory deficits in these patients.
Su et al. (2016) assessed the impact of Trpa1 and Trpv1 on behavioral and biochemical responses to iodine in mice in the presence or absence of specific antagonists. They found that Trpa1 is the major mediator of iodine-induced pain, with Trpv1 accounting for the remainder. Iodine-induced nociceptive responses were substantially attenuated in mice lacking Trpa1. Further analysis showed that the substance P (162320) rather than the CGRP (114130) signaling pathway was involved in the adjuvant effect of iodine on cutaneous allergy. In human cells, TRPA1, but not TRPV1, was directly activated by iodine. Su et al. (2016) proposed that local inhibition of TRPA1 and TRPV1 channels may minimize the side effects of iodine antiseptics while retaining their superior antimicrobial efficacy and lack of acquired microbial resistance.
Xue et al. (2001) determined that the TRPV1 gene contains 16 exons, with several alternate first exons encoding the 5-prime untranslated region. The initiation ATG is located within exon 2.
Cortright et al. (2001) determined that the human TRPV1 gene contains 18 exons and spans at least 32 kb.
By sequencing 200 kb surrounding the CTNS gene (606272) on chromosome 17, Touchman et al. (2000) mapped the VR1 gene to 17p13. Using radiation hybrid analysis, Hayes et al. (2000) mapped the TRPV1 gene to chromosome 17p13.
Liedtke et al. (2000) mapped the mouse Vr1 gene to chromosome 11 by interspecific backcross analysis.
Crystal Structure
Liao et al. (2013) exploited advances in electron cryomicroscopy to determine the structure of a mammalian TRP channel, TRPV1, at 3.4-angstrom resolution, breaking the side chain resolution barrier for membrane proteins without crystallization. Like voltage-gated channels, TRPV1 exhibits 4-fold symmetry around a central ion pathway formed by transmembrane segments 5 and 6 (S5-S6) and the intervening pore loop, which is flanked by S1-S4 voltage sensor-like domains. TRPV1 has a wide extracellular 'mouth' with a short selectivity filter. The conserved TRP domain interacts with the S4-S5 linker, consistent with its contribution to allosteric modulation. Subunit organization is facilitated by interactions among cytoplasmic domains, including amino-terminal ankyrin repeats. Liao et al. (2013) concluded that these observations provided a structural blueprint for understanding unique aspects of TRP channel function.
Cao et al. (2013) exploited pharmacologic probes to determine structures of 2 activated states of the capsaicin receptor, TRPV1. A domain (consisting of transmembrane segments 1 through 4) that moves during activation of voltage-gated channels remains stationary in TRPV1, highlighting differences in gating mechanisms for these structurally related channel superfamilies. TRPV1 opening is associated with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism. Allosteric coupling between upper and lower gates may account for the rich physiologic modulation exhibited by TRPV1 and other TRP channels.
Using electron cryomicroscopy and lipid nanodisc technology, Gao et al. (2016) determined the structure of the rat Trpv1 ion channel in a native bilayer environment. Gao et al. (2016) determined the locations of annular and regulatory lipids and showed that specific phospholipid interactions enhance binding of a spider toxin to Trpv1 through formation of a tripartite complex. Furthermore, phosphatidylinositol lipids occupy the binding site for capsaicin and other vanilloid ligands, suggesting a mechanism whereby chemical or thermal stimuli elicit channel activation by promoting the release of bioactive lipids from a critical allosteric regulatory site.
Vampire bats can detect infrared radiation and thereby locate hot spots on warm-blooded prey by means of trigeminal nerve fibers that innervate specialized pit organs surrounding their nose. Gracheva et al. (2011) found that trigeminal ganglia (TG) of vampire bats, like those of pit-bearing snakes, are larger in diameter than those of fruit bats and other mammals, whereas dorsal root ganglia (DRG) are similar to those of fruit bats. They showed that vampire bats express a Trpv1 splice variant exclusively in TG that encodes a Trpv1 isoform with a truncated C-terminal cytoplasmic domain. This variation within the Trpv1 C terminus enables the already heat-sensitive channel to have an expression threshold of about 30 degrees centrigrade. Gracheva et al. (2011) showed that a similar strategy is used by other vertebrates to adapt to specific environments. Analysis of TRP channel gene structure provided a physiologically relevant marker for assessing phylogenetic relationships, in this case grouping bats with horses, dogs, cows, moles, and dolphins in the Laurasiatheria superorder, rather than with humans and other members of the Euarchontoglires superorder.
Caterina et al. (2000) generated mice deficient in VR1 by targeted disruption. Vr1 -/- mice were viable, fertile, and largely indistinguishable from wildtype littermates. Caterina et al. (2000) demonstrated that sensory neurons from mice lacking VR1 are severely deficient in their responses to vanilloid compounds, protons, or heat greater than 43 degrees C. Vr1 -/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, Caterina et al. (2000) concluded that VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.
Birder et al. (2002) noted that Trpv1 is expressed in nerve fibers within the rat urinary bladder muscularis, submucosa, and mucosa. They developed Trpv1-null mice and found that, while anatomically normal, these mice had more frequent low-amplitude bladder activity than normal mice. Bladder capacity was increased in Trpv1-null mice relative to wildtype mice. In vitro, the excised bladder showed impaired responsiveness to mechanical stretch, and cultured urothelial cells showed impaired responsiveness to hypotonicity. Birder et al. (2002) concluded that TRPV1 has a role in normal bladder function, particularly in the detection of mechanical stimuli by the urothelium.
Basu and Srivastava (2005) found that mouse Vr1 was present not only on nociceptive neurons, but also on dendritic cells (DCs). Treatment of immature DCs from wildtype mice with capsaicin led to DC maturation with upregulation of antigen-presenting and costimulatory molecules. This effect was not present in Vr1 -/- mice and could be inhibited in wildtype mice by the VR1 antagonist, capsazepine. Capsaicin administered intradermally induced DC migration to draining lymph nodes in wildtype but not Vr1 -/- mice. Basu and Srivastava (2005) concluded that VR1 is an example of a common receptor in the nervous and immune systems and suggested that there may be a nexus between nutrition and immunity.
Using immunohistochemistry, Razavi et al. (2006) showed that mouse pancreatic islets, but not endocrine islets, were associated with meshworks of Trpv1-positive fibers. Treatment of neonatal mice with capsaicin permanently removed these neurons and eliminated Trpv1 expression. Elimination of these neurons in diabetes-prone NOD mice prevented insulitis and diabetes despite the persistence of pathogenic T-cell pools that would normally mediate pancreatic beta-cell death. Insulin resistance and beta-cell stress of prediabetic NOD mice were prevented by elimination of Trpv1-positive neurons. Intraarterial, but not intravenous, injection of substance P (162320) into NOD pancreas reversed the abnormal insulin resistance, insulitis, and diabetes for weeks. Trpv1 -/- mice had enhanced insulin sensitivity, whereas NOD mice carrying the wildtype Idd4.1 mouse diabetes risk locus and wildtype Trpv1 showed restored Trpv1 function and insulin sensitivity. Razavi et al. (2006) concluded that insulin-responsive TRPV1-positive sensory neurons have a fundamental role in beta-cell function and in the etiology of diabetes pathology.
Vandewauw et al. (2018) showed that acute noxious heat sensing in mice depends on a triad of transient receptor potential ion channels: Trpm3 (608961), Trpv1, and Trpa1 (604775). Vandewauw et al. (2018) found that robust somatosensory heat responsiveness at the cellular and behavioral level is observed only if at least 1 of these TRP channels is functional. However, combined genetic or pharmacologic elimination of all 3 channels largely and selectively prevents heat responses in both isolated sensory neurons and rapidly firing C and A-delta sensory nerve fibers that innervate the skin. Strikingly, Trpv1-/-Trpm3-/-Trpa1-/- triple-knockout mice lack the acute withdrawal response to noxious heat that is necessary to avoid burn injury, while showing normal nociceptive responses to cold or mechanical stimuli and a preserved preference for moderate temperatures. Vandewauw et al. (2018) concluded their findings indicated that the initiation of the acute heat-evoked pain response in sensory nerve endings relies on 3 functionally redundant TRP channels, representing a fault-tolerant mechanism to avoid burn injury.
Bartoshuk, L. M., Duffy, V. B., Miller, I. J. PTC/PROP tasting: anatomy, psychophysics, and sex effects. Physiol. Behav. 56: 1165-1171, 1994. Note: Erratum: Physiol. Behav. 58: 203 only, 1995. [PubMed: 7878086] [Full Text: https://doi.org/10.1016/0031-9384(94)90361-1]
Basu, S., Srivastava, P. Immunological role of neuronal receptor vanilloid receptor 1 expressed on dendritic cells. Proc. Nat. Acad. Sci. 102: 5120-5125, 2005. [PubMed: 15793000] [Full Text: https://doi.org/10.1073/pnas.0407780102]
Bhave, G., Zhu, W., Wang, H., Brasier, D. J., Oxford, G. S., Gereau, R. W., IV. cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation. Neuron 35: 721-731, 2002. [PubMed: 12194871] [Full Text: https://doi.org/10.1016/s0896-6273(02)00802-4]
Binshtok, A. M., Bean, B. P., Woolf, C. J. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449: 607-610, 2007. [PubMed: 17914397] [Full Text: https://doi.org/10.1038/nature06191]
Birder, L. A., Nakamura, Y., Kiss, S., Nealen, M. L., Barrick, S., Kanai, A. J., Wang, E., Ruiz, G., de Groat, W. C., Apodaca, G., Watkins, S., Caterina, M. J. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nature Neurosci. 5: 856-860, 2002. [PubMed: 12161756] [Full Text: https://doi.org/10.1038/nn902]
Bohlen, C. J., Priel, A., Zhou, S., King, D., Siemens, J., Julius, D. A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell 141: 834-845, 2010. [PubMed: 20510930] [Full Text: https://doi.org/10.1016/j.cell.2010.03.052]
Buntinx, L., Voets, T., Morlion, B., Vangeel, L., Janssen, M., Cornelissen, E., Vriens, J., de Hoon, J., Levtchenko, E. TRPV1 dysfunction in cystinosis patients harboring the homozygous 57 kb deletion. Sci. Rep. 6: 35395, 2016. Note: Electronic Article. [PubMed: 27734949] [Full Text: https://doi.org/10.1038/srep35395]
Cao, E., Liao, M., Cheng, Y., Julius, D. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504: 113-118, 2013. [PubMed: 24305161] [Full Text: https://doi.org/10.1038/nature12823]
Caterina, M. J., Leffler, A., Malmberg, A. B., Martin, W. J., Trafton, J., Petersen-Zeltz, K. R., Koltzenburg, M., Basbaum, A. I., Julius, D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288: 306-313, 2000. [PubMed: 10764638] [Full Text: https://doi.org/10.1126/science.288.5464.306]
Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., Julius, D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389: 816-824, 1997. [PubMed: 9349813] [Full Text: https://doi.org/10.1038/39807]
Chan, C. L. H., Facer, P., Davis, J. B., Smith, G. D., Egerton, J., Bountra, C., Williams, N. S., Anand, P. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet 361: 385-391, 2003. [PubMed: 12573376] [Full Text: https://doi.org/10.1016/s0140-6736(03)12392-6]
Chuang, H., Prescott, E. D., Kong, H., Shields, S., Jordt, S.-E., Basbaum, A. I., Chao, M. V., Julius, D. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411: 957-962, 2001. [PubMed: 11418861] [Full Text: https://doi.org/10.1038/35082088]
Cortright, D. N., Crandall, M., Sanchez, J. F., Zou, T., Krause, J. E., White, G. The tissue distribution and functional characterization of human VR1. Biochem. Biophys. Res. Commun. 281: 1183-1189, 2001. [PubMed: 11243859] [Full Text: https://doi.org/10.1006/bbrc.2001.4482]
Gao, Y., Cao, E., Julius, D., Cheng, Y. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature 534: 347-351, 2016. [PubMed: 27281200] [Full Text: https://doi.org/10.1038/nature17964]
Gracheva, E. O., Cordero-Morales, J. F., Gonzalez-Carcacia, J. A., Ingolia, N. T., Manno, C., Aranguren, C. I., Weissman, J. S., Julius, D. Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats. Nature 476: 88-91, 2011. [PubMed: 21814281] [Full Text: https://doi.org/10.1038/nature10245]
Hayes, P., Meadows, H. J., Gunthorpe, M. J., Harries, M. H., Duckworth, D. M., Cairns, W., Harrison, D. C., Clarke, C. E., Ellington, K., Prinjha, R. K., Barton, A. J. L., Medhurst, A. D., and 10 others. Cloning and functional expression of a human orthologue of rat vanilloid receptor-1. Pain 88: 205-215, 2000. [PubMed: 11050376] [Full Text: https://doi.org/10.1016/S0304-3959(00)00353-5]
Jordt, S.-E., Julius, D. Molecular basis for species-specific sensitivity to 'hot' chili peppers. Cell 108: 421-430, 2002. [PubMed: 11853675] [Full Text: https://doi.org/10.1016/s0092-8674(02)00637-2]
Kim, A. Y., Tang, Z., Liu, Q., Patel, K. N., Maag, D., Geng, Y., Dong, X. Pirt, a phosphoinositide-binding protein, functions as a regulatory subunit of TRPV1. Cell 133: 475-485, 2008. [PubMed: 18455988] [Full Text: https://doi.org/10.1016/j.cell.2008.02.053]
Liao, M., Cao, E., Julius, D., Chen, Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504: 107-112, 2013. [PubMed: 24305160] [Full Text: https://doi.org/10.1038/nature12822]
Liedtke, W., Choe, Y., Marti-Renom, M. A., Bell, A. M., Denis, C. S., Sali, A., Hudspeth, A. J., Friedman, J. M., Heller, S. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103: 525-535, 2000. [PubMed: 11081638] [Full Text: https://doi.org/10.1016/s0092-8674(00)00143-4]
Liu, L., Simon, S. A. Similarities and differences in the currents activated by capsaicin, piperine, and zingerone in rat trigeminal ganglion cells. J. Neurophysiol. 76: 1858-1869, 1996. [PubMed: 8890298] [Full Text: https://doi.org/10.1152/jn.1996.76.3.1858]
Macpherson, L. J., Geierstanger, B. H., Viswanath, V., Bandell, M., Eid, S. R., Hwang, S., Patapoutian, A. The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr. Biol. 15: 929-934, 2005. [PubMed: 15916949] [Full Text: https://doi.org/10.1016/j.cub.2005.04.018]
Numazaki, M., Tominaga, T., Toyooka, H., Tominaga, M. Direct phosphorylation of capsaicin receptor VR1 by protein kinase C epsilon and identification of two target serine residues. J. Biol. Chem. 277: 13375-13378, 2002. [PubMed: 11884385] [Full Text: https://doi.org/10.1074/jbc.C200104200]
Premkumar, L. S., Ahern, G. P. Induction of vanilloid receptor channel activity by protein kinase C. Nature 408: 985-990, 2000. [PubMed: 11140687] [Full Text: https://doi.org/10.1038/35050121]
Prescott, E. D., Julius, D. A modular PIP-2 binding site as a determinant of capsaicin receptor sensitivity. Science 300: 1284-1288, 2003. [PubMed: 12764195] [Full Text: https://doi.org/10.1126/science.1083646]
Prescott, J., Stevenson, R. J. Psychophysical responses to single and multiple presentations of the oral irritant zingerone: relationship to frequency of chili consumption. Physiol. Behav. 60: 617-624, 1996. [PubMed: 8840926] [Full Text: https://doi.org/10.1016/s0031-9384(96)80039-4]
Razavi, R., Chan, Y., Afifiyan, F. N., Liu, X. J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., Santamaria, P., Driver, J. P., Serreze, D., Salter, M. W., Dosch, H.-M. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell 127: 1123-1135, 2006. [PubMed: 17174891] [Full Text: https://doi.org/10.1016/j.cell.2006.10.038]
Riol-Blanco, L., Ordovas-Montanes, J., Perro, M., Naval, E., Thiriot, A., Alvarez, D., Paust, S., Wood, J. N., von Andrian, U. H. Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. Nature 510: 157-161, 2014. [PubMed: 24759321] [Full Text: https://doi.org/10.1038/nature13199]
Siemens, J., Zhou, S., Piskorowski, R., Nikai, T., Lumpkin, E. A., Basbaum, A. I., King, D., Julius, D. Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 444: 208-212, 2006. [PubMed: 17093448] [Full Text: https://doi.org/10.1038/nature05285]
Stevenson, R. J., Prescott, J. The effects of prior experience with capsaicin on ratings of its burn. Chem. Senses 19: 651-656, 1994. [PubMed: 7735844] [Full Text: https://doi.org/10.1093/chemse/19.6.651]
Stevenson, R. J., Yeomans, M. R. Differences in ratings of intensity and pleasantness for the capsaicin burn between chili likers and non-likers: implications for liking development. Chem. Senses 18: 471-482, 1993.
Su, D., Zhao, H., Hu, J., Tang, D., Cui, J., Zhou, M., Yang, J., Wang, S. TRPA1 and TRPV1 contribute to iodine antiseptics-associated pain and allergy. EMBO Rep. 17: 1422-1430, 2016. [PubMed: 27566753] [Full Text: https://doi.org/10.15252/embr.201642349]
Touchman, J. W., Anikster, Y., Dietrich, N. L., Braden Maduro, V. V., McDowell, G., Shotelersuk, V., Bouffard, G. G., Beckstrom-Sternberg, S. M., Gahl, W. A., Green, E. D. The genomic region encompassing the nephropathic cystinosis gene (CTNS): complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion. Genome Res. 10: 165-173, 2000. [PubMed: 10673275] [Full Text: https://doi.org/10.1101/gr.10.2.165]
Trevisani, M., Smart, D., Gunthorpe, M. J., Tognetto, M., Barbieri, M., Campi, B., Amadesi, S., Gray, J., Jerman, J. C., Brough, S. J., Owen, D., Smith, G. D., Randall, A. D., Harrison, S., Bianchi, A., Davis, J. B., Geppetti, P. Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nature Neurosci. 5: 546-551, 2002. [PubMed: 11992116] [Full Text: https://doi.org/10.1038/nn0602-852]
Vandewauw, I., De Clercq, K., Mulier, M., Held, K., Pinto, S., Van Ranst, N., Segal, A., Voet, T., Vennekens, R., Zimmermann, K., Vriens, J., Voets, T. A TRP channel trio mediates acute noxious heat sensing. Nature 555: 662-666, 2018. Note: Erratum: Nature 559: e7, 2018. Electronic Article. [PubMed: 29539642] [Full Text: https://doi.org/10.1038/nature26137]
Voets, T., Droogmans, G., Wissenbach, U., Janssens, A., Flockerzi, V., Nilius, B. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430: 748-754, 2004. [PubMed: 15306801] [Full Text: https://doi.org/10.1038/nature02732]
Walker, K. M., Urban, L., Medhurst, S. J., Patel, S., Panesar, M., Fox, A. J., McIntyre, P. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J. Pharm. Exp. Ther. 304: 56-62, 2003. [PubMed: 12490575] [Full Text: https://doi.org/10.1124/jpet.102.042010]
Weng, H.-J., Patel, K. N., Jeske, N. A., Bierbower, S. M., Zou, W., Tiwari, V., Zheng, Q., Tang, Z., Mo, G. C. H., Wang, Y., Geng, Y., Zhang, J., Guan, Y., Akopian, A. N., Dong, X. Tmem100 is a regulator of TRPA1-TRPV1 complex and contributes to persistent pain. Neuron 85: 833-846, 2015. [PubMed: 25640077] [Full Text: https://doi.org/10.1016/j.neuron.2014.12.065]
Xue, Q., Yu, Y., Trilk, S. L., Jong, B. E., Schumacher, M. A. The genomic organization of the gene encoding the vanilloid receptor: evidence for multiple splice variants. Genomics 76: 14-20, 2001. [PubMed: 11549313] [Full Text: https://doi.org/10.1006/geno.2001.6582]