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Bernd Nilius - One of the best experts on this subject based on the ideXlab platform.
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Transient Receptor Potentials (TRPs) and Anaphylaxis
Current Allergy and Asthma Reports, 2013Co-Authors: Peter K. Smith, Bernd NiliusAbstract:The transient receptor potential (TRP) superfamily consists of 28 members in mammals (27 in human) that act as polymodal sensors and ion channels. They regulate cellular calcium influx, generate depolarization thereby triggering voltage dependent cellular processes, and in turn they are critical in inducing the metabolic activities of cells. It is increasingly apparent that many of the inflammatory mediators released in allergic reactions involve at least two of these ion channels, the ‘Vanilloid’ TRPV1 and the ‘Ankyrin” TRPA1. This review mainly focuses on TRPV1 and TRPA1 and the role they have in the allergic response and how these receptors may be influenced in exercise-induced anaphylaxis. The threshold to react to an allergen for mast cells and lymphocytes can be reduced by activating the melastatin channel TRPM4. This channel is briefly discussed in the context of allergy.
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transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole
The Journal of Neuroscience, 2008Co-Authors: Victor Meseguer, Bernd Nilius, Yuji Karashima, Karel Talavera, Dieter Dhoedt, Tansy Donovanrodriguez, Felix Viana, Thomas VoetsAbstract:Clotrimazole (CLT) is a widely used drug for the topical treatment of yeast infections of skin, vagina, and mouth. Common side effects of topical CLT application include irritation and burning pain of the skin and mucous membranes. Here, we provide evidence that transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of CLT. We found that clinically relevant CLT concentrations activate heterologously expressed TRPV1 and TRPA1, two TRP channels that act as receptors of irritant chemical and/or thermal stimuli in nociceptive neurons. In line herewith, CLT stimulated a subset of capsaicin-sensitive and mustard oil-sensitive trigeminal neurons, and evoked nocifensive behavior and thermal hypersensitivity with intraplantar injection in mice. Notably, CLT-induced pain behavior was suppressed by the TRPV1-antagonist BCTC [(N-(-4-tertiarybutylphenyl)-4-(3-cholorpyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide)] and absent in TRPV1-deficient mice. In addition, CLT inhibited the cold and menthol receptor TRPM8, and blocked menthol-induced responses in capsaicin- and mustard oil-insensitive trigeminal neurons. The concentration for 50% inhibition (IC50) of inward TRPM8 current was approximately 200 nM, making CLT the most potent known TRPM8 antagonist and a useful tool to discriminate between TRPM8- and TRPA1-mediated responses. Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects.
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transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole
The Journal of Neuroscience, 2008Co-Authors: Victor M Meseguer, Bernd Nilius, Yuji Karashima, Karel Talavera, Dieter Dhoedt, Tansy Donovanrodriguez, Felix Viana, Thomas VoetsAbstract:Clotrimazole (CLT) is a widely used drug for the topical treatment of yeast infections of skin, vagina, and mouth. Common side effects of topical CLT application include irritation and burning pain of the skin and mucous membranes. Here, we provide evidence that transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of CLT. We found that clinically relevant CLT concentrations activate heterologously expressed TRPV1 and TRPA1, two TRP channels that act as receptors of irritant chemical and/or thermal stimuli in nociceptive neurons. In line herewith, CLT stimulated a subset of capsaicin-sensitive and mustard oil-sensitive trigeminal neurons, and evoked nocifensive behavior and thermal hypersensitivity with intraplantar injection in mice. Notably, CLT-induced pain behavior was suppressed by the TRPV1-antagonist BCTC [( N -(-4-tertiarybutylphenyl)-4-(3-cholorpyridin-2-yl)tetrahydropyrazine-1(2 H )-carboxamide)] and absent in TRPV1-deficient mice. In addition, CLT inhibited the cold and menthol receptor TRPM8, and blocked menthol-induced responses in capsaicin- and mustard oil-insensitive trigeminal neurons. The concentration for 50% inhibition (IC50) of inward TRPM8 current was ∼200 nm, making CLT the most potent known TRPM8 antagonist and a useful tool to discriminate between TRPM8- and TRPA1-mediated responses. Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects.
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regulation of transient receptor potential trp channels by phosphoinositides
Pflügers Archiv: European Journal of Physiology, 2007Co-Authors: Tibor Rohacs, Bernd NiliusAbstract:This review summarizes the modulation of transient receptor potential (TRP) channels, by phosphoinositides. TRP channels are characterized by polymodal activation and a surprising complexity of regulation mechanisms. Possibly, most if not all TRP channels are modulated by phosphoinositides. Modulation by phosphatidylinositol 4,5-biphosphate (PIP2) has been shown in detail for TRP vanilloid (TRPV) 1, TRPV5, TRP melastatin (TRPM) 4, TRPM5, TRPM7, TRPM8, TRP polycystin 2, and the Drosophila TPR-like (TRPL) channels. This review describes mechanisms of modulation of TRP channels mainly by PIP2 and discusses some future challenges of this fascinating topic.
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molecular determinants of permeation through the cation channel trpv4
Journal of Biological Chemistry, 2002Co-Authors: Thomas Voets, Jean Prenen, Joris Vriens, Hiroyuki Watanabe, Annelies Janssens, Ulrich Wissenbach, Matthias Bodding, Guy Droogmans, Bernd NiliusAbstract:TRPM6 and its closest relative TRPM7 are members of the Transient Receptor Potential Melastatin (TRPM) subfamily of cation channels and are known to be Mg 2+ permeable. By aligning the sequence of the putative TRPM6 pore with the pore sequences of the other subfamily members, we located in the loop between the fifth and the sixth transmembrane domain, a stretch of amino acids residues, 1028 GEIDVC 1033 , as the potential selectivity filter. Two negatively charged residues, E 1024 (conserved in TRPM6, TRPM7, TRPM1 and TRPM3) and D 1031 (conserved along the entire TRPM subfamily), were identified as important determinants of cation permeation through TRPM6, because neutralization of both residues into an alanine resulted in non-functional channels. Neutralization of E 1029 (conserved in TRPM6, TRPM7, TRPM4 and TRPM5) resulted in channels with increased conductance for Ba 2+ and Zn 2+ , decreased ruthenium red sensitivity and larger pore diameter compared to wild-type TRPM6. Changing the residue I 1030 into methionine, resulted in channels with lower conductance for Ni 2+ , decreased sensitivity to ruthenium red block and reduced pore diameter. Thus, these data demonstrate that amino acid residues E 1024 ,I 1030 and D 1031 are important for channel function and that subtle amino acid variation in the pore region accounts for TRPM6 permeation properties.
Thomas Voets - One of the best experts on this subject based on the ideXlab platform.
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Transient receptor potential channels in sensory mechanisms of the lower urinary tract
Nature Reviews Urology, 2021Co-Authors: Matthias Vanneste, Thomas Voets, Andrei Segal, Wouter EveraertsAbstract:Transient receptor potential (TRP) channels have an important role in sensory mechanisms of the lower urinary tract. Vanneste et al. discuss the involvement of TRP channels in normal and abnormal bladder sensations and their potential as therapeutic targets. Disruptions to sensory pathways in the lower urinary tract commonly occur and can give rise to lower urinary tract symptoms (LUTS). The unmet clinical need for treatment of LUTS has stimulated research into the molecular mechanisms that underlie neuronal control of the bladder and transient receptor potential (TRP) channels have emerged as key regulators of the sensory processes that regulate bladder function. TRP channels function as molecular sensors in urothelial cells and afferent nerve fibres and can be considered the origin of bladder sensations. TRP channels in the lower urinary tract contribute to the generation of normal and abnormal bladder sensations through a variety of mechanisms, and have demonstrated potential as targets for the treatment of LUTS in functional disorders of the lower urinary tract. Transient receptor potential (TRP) channels are expressed throughout all layers of the bladder wall and their function is closely related to the location of expression. High urothelial expression of TRPM4, TRPM7 and TRPV4 has been observed, the latter of which is considered to be a stretch sensor in urothelial cells. TRPV1, TRPA1 and TRPM8 are expressed on afferent nerves in the bladder and are involved in changes in bladder function during inflammation (TRPV1 and TRPA1) or cold stimulation (TRPM8). Despite involvement of TRP channels in animal models for overactive bladder, underactive bladder and cold-induced LUTS, translation to clinical applications remains limited.
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volatile anaesthetics inhibit the thermosensitive nociceptor ion channel transient receptor potential melastatin 3 trpm3
Biochemical Pharmacology, 2020Co-Authors: Balazs Kelemen, Erika Lisztes, Anita Vladar, Martin Hanyicska, Janos Almassy, Attila Olah, Attila Gabor Szollősi, Zsofia Penzes, Janos Posta, Thomas VoetsAbstract:Abstract Background Volatile anaesthetics (VAs) are the most widely used compounds to induce reversible loss of consciousness and maintain general anaesthesia during surgical interventions. Although the mechanism of their action is not yet fully understood, it is generally believed, that VAs depress central nervous system functions mainly through modulation of ion channels in the neuronal membrane, including 2-pore-domain K+ channels, GABA and NMDA receptors. Recent research also reported their action on nociceptive and thermosensitive TRP channels expressed in the peripheral nervous system, including TRPV1, TRPA1, and TRPM8. Here, we investigated the effect of VAs on TRPM3, a less characterized member of the thermosensitive TRP channels playing a central role in noxious heat sensation. Methods We investigated the effect of VAs on the activity of recombinant and native TRPM3, by monitoring changes in the intracellular Ca2+ concentration and measuring TRPM3-mediated transmembrane currents. Results All the investigated VAs (chloroform, halothane, isoflurane, sevoflurane) inhibited both the agonist-induced (pregnenolone sulfate, CIM0216) and heat-activated Ca2+ signals and transmembrane currents in a concentration dependent way in HEK293T cells overexpressing recombinant TRPM3. Among the tested VAs, halothane was the most potent blocker (IC50 = 0.52 ± 0.05 mM). We also investigated the effect of VAs on native TRPM3 channels expressed in sensory neurons of the dorsal root ganglia. While VAs activated certain sensory neurons independently of TRPM3, they strongly and reversibly inhibited the agonist-induced TRPM3 activity. Conclusions These data provide a better insight into the molecular mechanism beyond the analgesic effect of VAs and propose novel strategies to attenuate TRPM3 dependent nociception.
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transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole
The Journal of Neuroscience, 2008Co-Authors: Victor Meseguer, Bernd Nilius, Yuji Karashima, Karel Talavera, Dieter Dhoedt, Tansy Donovanrodriguez, Felix Viana, Thomas VoetsAbstract:Clotrimazole (CLT) is a widely used drug for the topical treatment of yeast infections of skin, vagina, and mouth. Common side effects of topical CLT application include irritation and burning pain of the skin and mucous membranes. Here, we provide evidence that transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of CLT. We found that clinically relevant CLT concentrations activate heterologously expressed TRPV1 and TRPA1, two TRP channels that act as receptors of irritant chemical and/or thermal stimuli in nociceptive neurons. In line herewith, CLT stimulated a subset of capsaicin-sensitive and mustard oil-sensitive trigeminal neurons, and evoked nocifensive behavior and thermal hypersensitivity with intraplantar injection in mice. Notably, CLT-induced pain behavior was suppressed by the TRPV1-antagonist BCTC [(N-(-4-tertiarybutylphenyl)-4-(3-cholorpyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide)] and absent in TRPV1-deficient mice. In addition, CLT inhibited the cold and menthol receptor TRPM8, and blocked menthol-induced responses in capsaicin- and mustard oil-insensitive trigeminal neurons. The concentration for 50% inhibition (IC50) of inward TRPM8 current was approximately 200 nM, making CLT the most potent known TRPM8 antagonist and a useful tool to discriminate between TRPM8- and TRPA1-mediated responses. Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects.
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transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole
The Journal of Neuroscience, 2008Co-Authors: Victor M Meseguer, Bernd Nilius, Yuji Karashima, Karel Talavera, Dieter Dhoedt, Tansy Donovanrodriguez, Felix Viana, Thomas VoetsAbstract:Clotrimazole (CLT) is a widely used drug for the topical treatment of yeast infections of skin, vagina, and mouth. Common side effects of topical CLT application include irritation and burning pain of the skin and mucous membranes. Here, we provide evidence that transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of CLT. We found that clinically relevant CLT concentrations activate heterologously expressed TRPV1 and TRPA1, two TRP channels that act as receptors of irritant chemical and/or thermal stimuli in nociceptive neurons. In line herewith, CLT stimulated a subset of capsaicin-sensitive and mustard oil-sensitive trigeminal neurons, and evoked nocifensive behavior and thermal hypersensitivity with intraplantar injection in mice. Notably, CLT-induced pain behavior was suppressed by the TRPV1-antagonist BCTC [( N -(-4-tertiarybutylphenyl)-4-(3-cholorpyridin-2-yl)tetrahydropyrazine-1(2 H )-carboxamide)] and absent in TRPV1-deficient mice. In addition, CLT inhibited the cold and menthol receptor TRPM8, and blocked menthol-induced responses in capsaicin- and mustard oil-insensitive trigeminal neurons. The concentration for 50% inhibition (IC50) of inward TRPM8 current was ∼200 nm, making CLT the most potent known TRPM8 antagonist and a useful tool to discriminate between TRPM8- and TRPA1-mediated responses. Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects.
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molecular determinants of permeation through the cation channel trpv4
Journal of Biological Chemistry, 2002Co-Authors: Thomas Voets, Jean Prenen, Joris Vriens, Hiroyuki Watanabe, Annelies Janssens, Ulrich Wissenbach, Matthias Bodding, Guy Droogmans, Bernd NiliusAbstract:TRPM6 and its closest relative TRPM7 are members of the Transient Receptor Potential Melastatin (TRPM) subfamily of cation channels and are known to be Mg 2+ permeable. By aligning the sequence of the putative TRPM6 pore with the pore sequences of the other subfamily members, we located in the loop between the fifth and the sixth transmembrane domain, a stretch of amino acids residues, 1028 GEIDVC 1033 , as the potential selectivity filter. Two negatively charged residues, E 1024 (conserved in TRPM6, TRPM7, TRPM1 and TRPM3) and D 1031 (conserved along the entire TRPM subfamily), were identified as important determinants of cation permeation through TRPM6, because neutralization of both residues into an alanine resulted in non-functional channels. Neutralization of E 1029 (conserved in TRPM6, TRPM7, TRPM4 and TRPM5) resulted in channels with increased conductance for Ba 2+ and Zn 2+ , decreased ruthenium red sensitivity and larger pore diameter compared to wild-type TRPM6. Changing the residue I 1030 into methionine, resulted in channels with lower conductance for Ni 2+ , decreased sensitivity to ruthenium red block and reduced pore diameter. Thus, these data demonstrate that amino acid residues E 1024 ,I 1030 and D 1031 are important for channel function and that subtle amino acid variation in the pore region accounts for TRPM6 permeation properties.
Makoto Tominaga - One of the best experts on this subject based on the ideXlab platform.
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Involvement of thermosensitive TRP channels in energy metabolism
The Journal of Physiological Sciences, 2017Co-Authors: Kunitoshi Uchida, Katsuya Dezaki, Takeshi Yoneshiro, Jun Yamazaki, Toshihiko Yada, Makoto Tominaga, Masayuki Saito, Tatsuo Watanabe, Yusaku IwasakiAbstract:To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.
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4 isopropylcyclohexanol has potential analgesic effects through the inhibition of anoctamin 1 trpv1 and trpa1 channel activities
Scientific Reports, 2017Co-Authors: Yasunori Takayama, Makoto Tominaga, Hidemasa FurueAbstract:Interactions between calcium-activated chloride channel anoctamin 1 (ANO1) and transient receptor potential vanilloid 1 (TRPV1) enhance pain sensations in mice, suggesting that ANO1 inhibition could have analgesic effects. Here we show that menthol and the menthol analogue isopropylcyclohexane (iPr-CyH) inhibited ANO1 channels in mice. The iPr-CyH derivative 4-isopropylcyclohexanol (4-iPr-CyH-OH) inhibited mouse ANO1 currents more potently than iPr-CyH. Moreover, 4-iPr-CyH-OH inhibited the activities of TRPV1, TRP ankyrin 1 (TRPA1), TRP melastatin 8 (TRPM8) and TRPV4. Single-channel analysis revealed that 4-iPr-CyH-OH reduced TRPV1 and TRPA1 current open-times without affecting unitary amplitude or closed-time, suggesting that it affected gating rather than blocking the channel pore. The ability of 4-iPr-CyH-OH to inhibit action potential generation and reduce pain-related behaviors induced by capsaicin in mice suggests that 4-iPr-CyH-OH could have analgesic applications. Thus, 4-iPr-CyH-OH is a promising base chemical to develop novel analgesics that target ANO1 and TRP channels.
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5 10 thermal sensation cold and heat through thermosensitive trp channel activation
The Senses: A Comprehensive Reference, 2008Co-Authors: Makoto TominagaAbstract:We feel a wide range of temperatures spanning from cold to heat. Within this range, temperatures over about 43 °C and below about 15 °C evoke not only a thermal sensation, but also a feeling of pain. In mammals, six thermosensitive ion channels have been reported, all of which belong to the TRP (transient receptor potential) superfamily. These include TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPA1. These channels exhibit distinct thermal activation thresholds (>43 °C for TRPV1, >52 °C for TRPV2, >∼34–38 °C for TRPV3, >∼27–35 °C for TRPV4, <∼25–28 °C for TRPM8 and <17 °C for TRPA1) and are expressed in primary sensory neurons as well as in other tissues.
Zhong-hua Yang - One of the best experts on this subject based on the ideXlab platform.
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Distribution profiles of transient receptor potential melastatin- and vanilloid-related channels in rat spermatogenic cells and sperm.
Molecular Biology Reports, 2009Co-Authors: Xing-huan Wang, Wei-cheng Gao, Zhong-hua YangAbstract:In the present study, we aimed to investigate the expression and distribution of transient receptor potential melastatin (TRPM)- and vanilloid (TRPV)- related channels in rat spermatogenic cells and spermatozoa. Spermatogenic cells and spermatozoa were obtained from male Sprague-Dawley rats. Reverse transcription polymerase chain reaction (RT-PCR) were used to detect the expression of all TRPM and TRPV channel members with specific primers. Western blot analysis was applied for detecting the expression of TRPM and TRPV channel proteins. Immunohistochemistry staining for TRPM4, TRPM7 and TRPV5 was also performed in rat testis. The mRNAs of TRPM3, TRPM4, TRPM7 and TRPV5 were detected in the spermatogenic cells and spermatozoa in rat. Western blot analysis verified the expression of TRPM4, TRPM7 and TRPV5 in the rat spermatogenic cells and spermatozoa. Immunocytochemistry staining for TRPM and TRPV channel families indicated that TRPM4 and TRPM7 proteins were highly expressed in different stages of spermatogenic cells and spermatozoa, while TRPV5 protein was lowly expressed in these cells. Our results demonstrate that mRNAs or proteins for TRPM3, TRPM4, TRPM7 and TRPV5 exist in rat spermatogenic cells and spermatozoa. These data presented here may assist in elucidating the possible physiological function of TRPM and TRPV channels in spermatogenic cells and spermatozoa.
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Expression of TRPM and TRPV channel family mRNA in rat spermatogenic cells
Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 2008Co-Authors: Xing-huan Wang, Huai-peng Wang, Zhong-hua Yang, Wei-cheng GaoAbstract:OBJECTIVE To investigate the expression of transient receptor potential melastatin (TRPM) and transient receptor potential vanilloid (TRPV) channel family genes in rat spermatogenic cells. METHODS Rat spermatogenic cells were isolated by a mechanical procedure and the total RNA was extracted using TRIzol reagent. TRPM and TRPV channel family genes were amplified by RT-PCR and the presence of the target genes was detected by agarose gel electrophoresis. The relative gene expression levels were measured by real-time quantitative RT-PCR. RESULTS TRPV5, TRPM3, TRPM4 and TRPM7 mRNAs were expressed in rat spermatogenic cells, but TRPV1, TRPV2, TRPV3, TRPV4, TRPV6, TRPM1, TRPM2, TRPM5, TRPM6, TRPM7 and TRPM8 mRNAs were not detected. The relative expressions of TRPM and TRPV mRNA were determined by quantitative real-time RT-PCR. TRPM7 expression was the highest among all the TRPM subtypes in rat spermatogenic cells, at a level equivalent to (0.0430-/+0.0034)% of beta-actin expression. TRPM3 and TRPM4 were also highly expressed, but their expression levels were only approximately 56% and 63% of that of TRPM7, respectively. For the TRPV subfamily, only TRPV5 mRNA was abundantly expressed at the level of (0.0157-/+0.0029)% relative to that of beta-actin. CONCLUSION TRPV5, TRPM3, TRPM4 and TRPM7 mRNAs were coexpressed in spermatogenic cells in rats, among which TRPM4 and TRPM7 mRNA were expressed at high levels. TRPM4 and TRPM7 channels may be involved in the regulation of growth, differentiation and maturation of rat spermatogenic cells and are associated with the generation of the sperms.
David E Clapham - One of the best experts on this subject based on the ideXlab platform.
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citral sensing by transient receptor potential channels in dorsal root ganglion neurons
PLOS ONE, 2008Co-Authors: Joris Vriens, Stephanie C Stotz, Derek C Martyn, Jon Clardy, David E ClaphamAbstract:Transient receptor potential (TRP) ion channels mediate key aspects of taste, smell, pain, temperature sensation, and pheromone detection. To deepen our understanding of TRP channel physiology, we require more diverse pharmacological tools. Citral, a bioactive component of lemongrass, is commonly used as a taste enhancer, as an odorant in perfumes, and as an insect repellent. Here we report that citral activates TRP channels found in sensory neurons (TRPV1 and TRPV3, TRPM8, and TRPA1), and produces long-lasting inhibition of TRPV1–3 and TRPM8, while transiently blocking TRPV4 and TRPA1. Sustained citral inhibition is independent of internal calcium concentration, but is state-dependent, developing only after TRP channel opening. Citral's actions as a partial agonist are not due to cysteine modification of the channels nor are they a consequence of citral's stereoisoforms. The isolated aldehyde and alcohol cis and trans enantiomers (neral, nerol, geranial, and geraniol) each reproduce citral's actions. In juvenile rat dorsal root ganglion neurons, prolonged citral inhibition of native TRPV1 channels enabled the separation of TRPV2 and TRPV3 currents. We find that TRPV2 and TRPV3 channels are present in a high proportion of these neurons (94% respond to 2-aminoethyldiphenyl borate), consistent with our immunolabeling experiments and previous in situ hybridization studies. The TRPV1 activation requires residues in transmembrane segments two through four of the voltage-sensor domain, a region previously implicated in capsaicin activation of TRPV1 and analogous menthol activation of TRPM8. Citral's broad spectrum and prolonged sensory inhibition may prove more useful than capsaicin for allodynia, itch, or other types of pain involving superficial sensory nerves and skin.