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Intracellular Proton-mediated Activation of TRPV3 Channels Accounts for the Exfoliation Effect of α-Hydroxyl Acids on Keratinocytes*

  • Xu Cao
    Affiliations
    Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, China

    Department of Physiology and Membrane Biology, University of California School of Medicine, Davis, California 95616
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  • Fan Yang
    Affiliations
    Department of Physiology and Membrane Biology, University of California School of Medicine, Davis, California 95616
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  • Jie Zheng
    Correspondence
    To whom correspondence may be addressed. Tel.: 530-7521241
    Affiliations
    Department of Physiology and Membrane Biology, University of California School of Medicine, Davis, California 95616
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  • KeWei Wang
    Correspondence
    To whom correspondence may be addressed. Tel.: 8610-82805065
    Affiliations
    Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, China

    Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, Peking University School of Pharmaceutical Sciences, 38 Xueyuan Road, Beijing 100191, China
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  • Author Footnotes
    * This work was supported, in whole or in part, by National Institutes of Health Grant R01NS072377 (to J. Z.) and Research Grant 30970919 from the National Science Foundation of China, the Ministry of Education of China 111 Project China (B07001) (to K. W. W.), and the China Scholarship Council (to X. C.).
Open AccessPublished:June 07, 2012DOI:https://doi.org/10.1074/jbc.M112.364869
      Background: Little is known about how α-hydroxyl acids (AHAs) widely cause exfoliation to expose fresh skin cells.
      Results: Transient receptor potential vanilloid 3 (TRPV3) channel in keratinocytes is potently activated by intracellular acidification induced by glycolic acid.
      Conclusion: TRPV3-mediated proton-sensing and cell death in keratinocytes may serve as a molecular basis for the cosmetic use of AHAs.
      Significance: We describe a novel mechanism by which TRPV3 is activated by intracellular protons.

      Introduction

      α-Hydroxyl acids (AHAs)
      The abbreviations used are: AHA
      α-hydroxyl acid
      TRPV3
      transient receptor potential vanilloid 3
      2-APB
      2-aminoethyl diphenylborinate
      PI
      propidium iodide
      MPR
      membrane-proximal region.
      are a group of organic carboxylic compounds that act as proton donors and have profound effects on keratinization of the skin. AHAs are well known in the cosmetic industry for their use in chemical peels (
      • Vidt D.G.
      • Bergfeld W.F.
      Cosmetic use of α-hydroxy acids.
      ,
      • Tung R.C.
      • Bergfeld W.F.
      • Vidimos A.T.
      • Remzi B.K.
      α-Hydroxy acid-based cosmetic procedures. Guidelines for patient management.
      ), and for the reduction of wrinkles and the signs of aging, and improving the overall look and feel of the skin (
      • Clark 3rd, C.P.
      α-Hydroxy acids in skin care.
      ,
      • Kurtzweil P.
      α-Hydroxy acids for skin care.
      ,
      • Roenigk Jr., H.H.
      Treatment of the aging face.
      ). As topical compounds, AHAs are thought to penetrate the skin and cause exfoliation and the exposure of fresh skin cells. Glycolic acid, the smallest AHA molecule with the greatest bioavailability, penetrates the skin most easily, accounting for its popularity in cosmetic applications (
      • Moy L.S.
      • Murad H.
      • Moy R.L.
      Glycolic acid peels for the treatment of wrinkles and photoaging.
      ,
      • Moy L.S.
      • Howe K.
      • Moy R.L.
      Glycolic acid modulation of collagen production in human skin fibroblast cultures in vitro.
      ,
      • Bergfeld W.
      • Tung R.
      • Vidimos A.
      • Vellanki L.
      • Remzi B.
      • Stanton-Hicks U.
      Improving the cosmetic appearance of photoaged skin with glycolic acid.
      ). The bioavailability of glycolic acid usually depends on its concentration and hence the pH level it produces (
      • Kim S.J.
      • Won Y.H.
      The effect of glycolic acid on cultured human skin fibroblasts. Cell proliferative effect and increased collagen synthesis.
      ,
      • Thueson D.O.
      • Chan E.K.
      • Oechsli L.M.
      • Hahn G.S.
      The roles of pH and concentration in lactic acid-induced stimulation of epidermal turnover.
      ,
      • DiNardo J.C.
      • Grove G.L.
      • Moy L.S.
      Clinical and histological effects of glycolic acid at different concentrations and pH levels.
      ,
      • Gutknecht J.
      • Tosteson D.C.
      Diffusion of weak acids across lipid bilayer membranes. Effects of chemical reactions in the unstirred layers.
      ). Despite the importance and prevalence of glycolic acid and other AHAs, the mechanism by which they are sensed by the skin is poorly understood.
      TRPV3 is a Ca2+-permeable cation channel that is primarily expressed in keratinocytes of the skin (
      • Hamamoto T.
      • Takumida M.
      • Hirakawa K.
      • Takeno S.
      • Tatsukawa T.
      Localization of transient receptor potential channel vanilloid subfamilies in the mouse larynx.
      ,
      • Peier A.M.
      • Reeve A.J.
      • Andersson D.A.
      • Moqrich A.
      • Earley T.J.
      • Hergarden A.C.
      • Story G.M.
      • Colley S.
      • Hogenesch J.B.
      • McIntyre P.
      • Bevan S.
      • Patapoutian A.
      A heat-sensitive TRP channel expressed in keratinocytes.
      ), as well as in sensory neurons (
      • Xu H.
      • Ramsey I.S.
      • Kotecha S.A.
      • Moran M.M.
      • Chong J.A.
      • Lawson D.
      • Ge P.
      • Lilly J.
      • Silos-Santiago I.
      • Xie Y.
      • DiStefano P.S.
      • Curtis R.
      • Clapham D.E.
      TRPV3 is a calcium-permeable temperature-sensitive cation channel.
      ,
      • Smith G.D.
      • Gunthorpe M.J.
      • Kelsell R.E.
      • Hayes P.D.
      • Reilly P.
      • Facer P.
      • Wright J.E.
      • Jerman J.C.
      • Walhin J.P.
      • Ooi L.
      • Egerton J.
      • Charles K.J.
      • Smart D.
      • Randall A.D.
      • Anand P.
      • Davis J.B.
      TRPV3 is a temperature-sensitive vanilloid receptor-like protein.
      ) where its activation causes a feeling of warmth. Indeed, transient receptor potential vanilloid 3 (TRPV3) is activated by moderate heating (>33 °C) that is perceived by human as warm (
      • Peier A.M.
      • Reeve A.J.
      • Andersson D.A.
      • Moqrich A.
      • Earley T.J.
      • Hergarden A.C.
      • Story G.M.
      • Colley S.
      • Hogenesch J.B.
      • McIntyre P.
      • Bevan S.
      • Patapoutian A.
      A heat-sensitive TRP channel expressed in keratinocytes.
      ,
      • Xu H.
      • Ramsey I.S.
      • Kotecha S.A.
      • Moran M.M.
      • Chong J.A.
      • Lawson D.
      • Ge P.
      • Lilly J.
      • Silos-Santiago I.
      • Xie Y.
      • DiStefano P.S.
      • Curtis R.
      • Clapham D.E.
      TRPV3 is a calcium-permeable temperature-sensitive cation channel.
      ,
      • Smith G.D.
      • Gunthorpe M.J.
      • Kelsell R.E.
      • Hayes P.D.
      • Reilly P.
      • Facer P.
      • Wright J.E.
      • Jerman J.C.
      • Walhin J.P.
      • Ooi L.
      • Egerton J.
      • Charles K.J.
      • Smart D.
      • Randall A.D.
      • Anand P.
      • Davis J.B.
      TRPV3 is a temperature-sensitive vanilloid receptor-like protein.
      ,
      • Cheng W.
      • Yang F.
      • Liu S.
      • Colton C.K.
      • Wang C.
      • Cui Y.
      • Cao X.
      • Zhu M.X.
      • Sun C.
      • Wang K.
      • Zheng J.
      Heteromeric heat-sensitive transient receptor potential channels exhibit distinct temperature and chemical response.
      ). Organic chemicals such as 2-aminoethyl diphenylborinate (2-APB) (
      • Hu H.Z.
      • Gu Q.
      • Wang C.
      • Colton C.K.
      • Tang J.
      • Kinoshita-Kawada M.
      • Lee L.Y.
      • Wood J.D.
      • Zhu M.X.
      2-Aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3.
      ,
      • Chung M.K.
      • Lee H.
      • Mizuno A.
      • Suzuki M.
      • Caterina M.J.
      2-Aminoethoxydiphenyl borate activates and sensitizes the heat-gated ion channel TRPV3.
      ) and its structurally related compounds (

      Colton, C. K., Zhu, M. X. (2007) 2-Aminoethoxydiphenyl borate as a common activator of TRPV1, TRPV2, and TRPV3 channels. Handb. Exp. Pharmacol., 173–187

      ), plant-derived compounds such as camphor, thymol, and carvacrol (
      • Xu H.
      • Delling M.
      • Jun J.C.
      • Clapham D.E.
      Oregano, thyme, and clove-derived flavors and skin sensitizers activate specific TRP channels.
      ,
      • Moqrich A.
      • Hwang S.W.
      • Earley T.J.
      • Petrus M.J.
      • Murray A.N.
      • Spencer K.S.
      • Andahazy M.
      • Story G.M.
      • Patapoutian A.
      Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin.
      ), and unsaturated fatty acids can activate or potentiate TRPV3 (
      • Hu H.Z.
      • Xiao R.
      • Wang C.
      • Gao N.
      • Colton C.K.
      • Wood J.D.
      • Zhu M.X.
      Potentiation of TRPV3 channel function by unsaturated fatty acids.
      ). The expression of TRPV3 has been demonstrated in primary rodent keratinocytes and immortalized skin cells such as human HaCaT cells and mouse 308 keratonocytes (
      • Peier A.M.
      • Reeve A.J.
      • Andersson D.A.
      • Moqrich A.
      • Earley T.J.
      • Hergarden A.C.
      • Story G.M.
      • Colley S.
      • Hogenesch J.B.
      • McIntyre P.
      • Bevan S.
      • Patapoutian A.
      A heat-sensitive TRP channel expressed in keratinocytes.
      ,
      • Xu H.
      • Ramsey I.S.
      • Kotecha S.A.
      • Moran M.M.
      • Chong J.A.
      • Lawson D.
      • Ge P.
      • Lilly J.
      • Silos-Santiago I.
      • Xie Y.
      • DiStefano P.S.
      • Curtis R.
      • Clapham D.E.
      TRPV3 is a calcium-permeable temperature-sensitive cation channel.
      ,
      • Smith G.D.
      • Gunthorpe M.J.
      • Kelsell R.E.
      • Hayes P.D.
      • Reilly P.
      • Facer P.
      • Wright J.E.
      • Jerman J.C.
      • Walhin J.P.
      • Ooi L.
      • Egerton J.
      • Charles K.J.
      • Smart D.
      • Randall A.D.
      • Anand P.
      • Davis J.B.
      TRPV3 is a temperature-sensitive vanilloid receptor-like protein.
      ,
      • Chung M.K.
      • Lee H.
      • Mizuno A.
      • Suzuki M.
      • Caterina M.J.
      2-Aminoethoxydiphenyl borate activates and sensitizes the heat-gated ion channel TRPV3.
      ,
      • Bang S.
      • Yoo S.
      • Yang T.J.
      • Cho H.
      • Kim Y.G.
      • Hwang S.W.
      Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception.
      ,
      • Chung M.K.
      • Lee H.
      • Mizuno A.
      • Suzuki M.
      • Caterina M.J.
      TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes.
      ,
      • Chung M.K.
      • Lee H.
      • Caterina M.J.
      Warm temperatures activate TRPV4 in mouse 308 keratinocytes.
      ,
      • Borbíró I.
      • Lisztes E.
      • Tóth B.I.
      • Czifra G.
      • Oláh A.
      • Szöllosi A.G.
      • Szentandrássy N.
      • Nánási P.P.
      • Péter Z.
      • Paus R.
      • Kovács L.
      • Bíró T.
      Activation of transient receptor potential vanilloid-3 inhibits human hair growth.
      ,
      • Bang S.
      • Yoo S.
      • Yang T.J.
      • Cho H.
      • Hwang S.W.
      Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3.
      ), where it plays an important role in skin physiology such as thermosensation and nociception (
      • Moqrich A.
      • Hwang S.W.
      • Earley T.J.
      • Petrus M.J.
      • Murray A.N.
      • Spencer K.S.
      • Andahazy M.
      • Story G.M.
      • Patapoutian A.
      Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin.
      ,
      • Huang S.M.
      • Lee H.
      • Chung M.K.
      • Park U.
      • Yu Y.Y.
      • Bradshaw H.B.
      • Coulombe P.A.
      • Walker J.M.
      • Caterina M.J.
      Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2.
      ). Targeted deletion of TRPV3 in mice abolishes TRPV3 currents in keratinocytes. Noticeably, TRPV3 knock-out causes a wavy hair/curly whisker phenotype and erythroderma (also known as the red man syndrome), indicating that the TRPV3 channel is necessary and important for normal hair morphogenesis and epidermal barrier formation (
      • Cheng X.
      • Jin J.
      • Hu L.
      • Shen D.
      • Dong X.P.
      • Samie M.A.
      • Knoff J.
      • Eisinger B.
      • Liu M.L.
      • Huang S.M.
      • Caterina M.J.
      • Dempsey P.
      • Michael L.E.
      • Dlugosz A.A.
      • Andrews N.C.
      • Clapham D.E.
      • Xu H.
      TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation.
      ). Spontaneous autosomal dominant mutations in TRPV3 that result in constitutive channel activity can also cause hairlessness (
      • Asakawa M.
      • Yoshioka T.
      • Matsutani T.
      • Hikita I.
      • Suzuki M.
      • Oshima I.
      • Tsukahara K.
      • Arimura A.
      • Horikawa T.
      • Hirasawa T.
      • Sakata T.
      Association of a mutation in TRPV3 with defective hair growth in rodents.
      ), dermatitis, and inflammatory skin lesions in rodents (
      • Yoshioka T.
      • Imura K.
      • Asakawa M.
      • Suzuki M.
      • Oshima I.
      • Hirasawa T.
      • Sakata T.
      • Horikawa T.
      • Arimura A.
      Impact of the G573S substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice.
      ,
      • Steinhoff M.
      • Bíró T.
      A TR(I)P to pruritus research. Role of TRPV3 in inflammation and itch.
      ,
      • Imura K.
      • Yoshioka T.
      • Hirasawa T.
      • Sakata T.
      Role of TRV3 in immune response to development of dermatitis.
      ). We have recently identified three genetic gain-of-function mutations located in the S4–S5 linker and C terminus of TRPV3 that cause Olmsted syndrome, characterized by bilateral multilating palmoplantar keratoderma and periorificial keratotic plaques with severe itching at lesions (
      • Lin Z.
      • Chen Q.
      • Lee M.
      • Cao X.
      • Zhang J.
      • Ma D.
      • Chen L.
      • Hu X.
      • Wang H.
      • Wang X.
      • Zhang P.
      • Liu X.
      • Guan L.
      • Tang Y.
      • Yang H.
      • Tu P.
      • Bu D.
      • Zhu X.
      • Wang K.
      • Li R.
      • Yang Y.
      Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.
      ). All these investigations indicate that overactive TRPV3 mediates an important role in skin physiology and pathophysiology. Furthermore, the TRPV3-activator carvacrol has been shown to boost collagen expression in the skin (
      • Lee J.
      • Jung E.
      • Yu H.
      • Kim Y.
      • Ha J.
      • Kim Y.S.
      • Park D.
      Mechanisms of carvacrol-induced expression of type I collagen gene.
      ). Interestingly, glycolic acid also promotes collagen synthesis in skin (
      • Moy L.S.
      • Howe K.
      • Moy R.L.
      Glycolic acid modulation of collagen production in human skin fibroblast cultures in vitro.
      ,
      • Kim S.J.
      • Won Y.H.
      The effect of glycolic acid on cultured human skin fibroblasts. Cell proliferative effect and increased collagen synthesis.
      ,
      • Montell C.
      Preventing a Perm with TRPV3.
      ), indicating a role for TRPV3 in glycolic acid-mediated processes (
      • Moy L.S.
      • Howe K.
      • Moy R.L.
      Glycolic acid modulation of collagen production in human skin fibroblast cultures in vitro.
      ,
      • Kim S.J.
      • Won Y.H.
      The effect of glycolic acid on cultured human skin fibroblasts. Cell proliferative effect and increased collagen synthesis.
      ,
      • Montell C.
      Preventing a Perm with TRPV3.
      ). Taken together, these observations raise the question of whether AHAs can affect the skin physiology by directly modulating the function of TRPV3 channel. To understand the molecular mechanism by which topical AHAs affect the epidermis and keratinization of the skin, we investigated the proton effect on TRPV3 function.
      Here we report that glycolic acid can strongly activate the TRPV3 channel. This activation is partially mediated by intracellular protons that act on His-426, located at the distal N terminus. Our findings demonstrate a novel gating mechanism by which TRPV3 is directly activated by intracellular acidification, likely accounting for the cosmetic effect of AHAs on keratinization of the skin.

      DISCUSSION

      Weak acids from normal cellular metabolites, whereas not toxic under physiological conditions, can lead to intracellular acidification in a concentration and extracellular pH-dependent fashion (
      • Gutknecht J.
      • Tosteson D.C.
      Diffusion of weak acids across lipid bilayer membranes. Effects of chemical reactions in the unstirred layers.
      ,
      • Gutknecht J.
      Aspirin, acetaminophen, and proton transport through phospholipid bilayers and mitochondrial membranes.
      ,
      • Maidorn R.P.
      • Cragoe Jr., E.J.
      • Tannock I.F.
      Therapeutic potential of analogues of amiloride. Inhibition of the regulation of intracellular pH as a possible mechanism of tumor selective therapy.
      ,
      • Karuri A.R.
      • Dobrowsky E.
      • Tannock I.F.
      Selective cellular acidification and toxicity of weak organic acids in an acidic microenvironment.
      ,
      • Wang Y.Y.
      • Chang R.B.
      • Allgood S.D.
      • Silver W.L.
      • Liman E.R.
      A TRPA1-dependent mechanism for the pungent sensation of weak acids.
      ). In this study, we demonstrated that glycolic acid-induced intracellular acidification could lead to TRPV3 activation. We suggest that glycolic acid may cause intracellular acidification in two ways (Fig. 8). In its neutral form, glycolic acid may cross the cell membrane to reach the cytosol where it re-equilibrates and releases the proton. Alternatively, protons can pass through the open TRPV3 channel or other proton-permeant pathways. These two processes may work cooperatively in TRPV3-expressing cells, as an increase in intracellular proton concentration through the first pathway would activate TRPV3 to promote the second pathway. As TRPV3 has a high Ca2+ permeability, elevated TRPV3 activity may cause intracellular Ca2+ overload that affects many aspects of cellular physiology and eventually causes cell death. Our findings reveal a novel mechanism by which TRPV3 is regulated by intracellular acidification through a coupling between cytosolic proton and Ca2+. This mechanism may help explain the cosmetic effect of weak acids on proliferation and an early phase of apoptosis in keratinocytes for skin renewal (Fig. 8). Therefore, pH sensing by TRPV3 may serve as an important mechanism in medical applications of topical AHAs such as glycolic acid on the skin.
      Figure thumbnail gr8
      FIGURE 8A model for functional activation of TRPV3 by AHAs. Weak acids such as glycolic acid can diffuse across the cell membrane in the protonated form, and then re-equilibrate to generate a free proton, causing intracellular acidification and activation of TRPV3 (pathway 1). Protons can also pass through activated TRPV3 or other proton-permeable channels to induce intracellular acidification and TRPV3 activation (pathway 2). TRPV3 activation mediates Ca2+ influx, leading to cytosolic Ca2+ overload, keratinization, and cell death.
      The detailed molecular mechanism underlying intracellular proton activation of TRPV3 remains to be elucidated. Our results suggest that His-426 plays an important role in proton-mediated activation of TRPV3. His-426 resides in the N-terminal membrane-proximal region (MPR), located between the last ankyrin repeat domain and the first transmembrane domain. MPR is an important region involved in different modes of TRPV1–4 activation. Especially, His-426 in the MPR of TRPV3 plays a critical role in 2-APB-induced channel activation (
      • Hu H.
      • Grandl J.
      • Bandell M.
      • Petrus M.
      • Patapoutian A.
      Two amino acid residues determine 2-APB sensitivity of the ion channels TRPV3 and TRPV4.
      ). The corresponding amino acid, His-378, in the MPR of TRPV1 has been shown to affect the intracellular alkalization-induced activation (
      • Dhaka A.
      • Uzzell V.
      • Dubin A.E.
      • Mathur J.
      • Petrus M.
      • Bandell M.
      • Patapoutian A.
      TRPV1 is activated by both acidic and basic pH.
      ). Yao et al. (
      • Yao J.
      • Liu B.
      • Qin F.
      Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels.
      ) recently reported that MPR might be the heat sensor of TRPVs, as swapping MPRs between TRPV channels led to a switch of the temperature sensitivity. These results suggest MPR is a shared functional element important for the activation of TRPV channels. Protonation of His-426 in the MPR is thus expected to affect TRPV3 activity by directly interacting with the activation process. However, we cannot rule out other potential site(s) besides His-426 that may be involved in the proton sensing.
      Besides providing a viable explanation of the cosmetic effect of topical AHAs, what is the physiological and pathophysiological significance of TRPV3 proton sensing? Variations in the pH level occurs in normal physiological processes such as respiratory and metabolic acidosis and alkalosis; it can be much more severe under pathological conditions such as tissue damage, inflammation, and ischemia (
      • Boron W.F.
      ). Cell acidification can serve as a concomitant of cell death (
      • Gottlieb R.A.
      • Nordberg J.
      • Skowronski E.
      • Babior B.M.
      Apoptosis induced in Jurkat cells by several agents is preceded by intracellular acidification.
      ) and a means to detect painful conditions, especially in deep tissues where the temperature is expected to remain constant (
      • Tominaga M.
      • Caterina M.J.
      • Malmberg A.B.
      • Rosen T.A.
      • Gilbert H.
      • Skinner K.
      • Raumann B.E.
      • Basbaum A.I.
      • Julius D.
      The cloned capsaicin receptor integrates multiple pain-producing stimuli.
      ). A number of TRP channels have been shown to be quite sensitive to changes in extracellular pH (
      • Ryu S.
      • Liu B.
      • Yao J.
      • Fu Q.
      • Qin F.
      Uncoupling proton activation of valloinoid receptor TRPV1.
      ,
      • Aneiros E.
      • Cao L.
      • Papakosta M.
      • Stevens E.
      • Phillips S.
      • Grimm C.
      ). Although intracellular acidification-mediated inhibition has been observed in TRPV5 and TRPM2 channels (
      • Du J.
      • Xie J.
      • Yue L.
      Modulation of TRPM2 by acidic pH and the underlying mechanisms for pH sensitivity.
      ,
      • Yeh B.I.
      • Kim Y.K.
      • Jabbar W.
      • Huang C.L.
      Conformational changes of pore helix coupled to gating of TRPV5 by protons.
      ), our findings represent the first demonstration of intracellular acidification-mediated activation by a member of the TRPV channel family.
      Besides being expressed in skin keratinocytes, TRPV3 is also expressed in various areas of the nervous system such as dorsal root ganglion, trigeminal ganglion, spinal cord, and brain (
      • Peier A.M.
      • Reeve A.J.
      • Andersson D.A.
      • Moqrich A.
      • Earley T.J.
      • Hergarden A.C.
      • Story G.M.
      • Colley S.
      • Hogenesch J.B.
      • McIntyre P.
      • Bevan S.
      • Patapoutian A.
      A heat-sensitive TRP channel expressed in keratinocytes.
      ,
      • Smith G.D.
      • Gunthorpe M.J.
      • Kelsell R.E.
      • Hayes P.D.
      • Reilly P.
      • Facer P.
      • Wright J.E.
      • Jerman J.C.
      • Walhin J.P.
      • Ooi L.
      • Egerton J.
      • Charles K.J.
      • Smart D.
      • Randall A.D.
      • Anand P.
      • Davis J.B.
      TRPV3 is a temperature-sensitive vanilloid receptor-like protein.
      ). Acidosis is a noxious condition associated with inflammation, ischemia, or defective acid containment. Among several acid-sensitive ion channels, acid-sensing ion channels and TRPV1 have been proposed to sense acid-mediated nociception (
      • Leffler A.
      • Mönter B.
      • Koltzenburg M.
      The role of the capsaicin receptor TRPV1 and acid-sensing ion channels (ASICS) in proton sensitivity of subpopulations of primary nociceptive neurons in rats and mice.
      ,
      • Smith E.S.
      • Lewin G.R.
      Nociceptors, a phylogenetic view.
      ,
      • Jones N.G.
      • Slater R.
      • Cadiou H.
      • McNaughton P.
      • McMahon S.B.
      Acid-induced pain and its modulation in humans.
      ). Acid-sensing ion channels detect moderate decreases in extracellular pH (
      • Shimada S.
      • Yamamura H.
      • Ueda T.
      • Yamamoto T.
      • Ugawa S.
      Functional analysis of acid sensing ion channels.
      ), whereas TRPV1 is activated only by severe acidosis resulting in pH values below 6 (
      • Jordt S.E.
      • Tominaga M.
      • Julius D.
      Acid potentiation of the capsaicin receptor determined by a key extracellular site.
      ). Both acid-sensing ion channels and TRPV1 exhibit very rapid desensitization and only produce a transient current response (
      • Moran M.M.
      • McAlexander M.A.
      • Bíró T.
      • Szallasi A.
      Transient receptor potential channels as therapeutic targets.
      ,
      • Nassini R.
      • Materazzi S.
      • De Siena G.
      • De Cesaris F.
      • Geppetti P.
      Transient receptor potential channels as novel drug targets in respiratory diseases.
      ,
      • Gunthorpe M.J.
      • Szallasi A.
      Peripheral TRPV1 receptors as targets for drug development. New molecules and mechanisms.
      ). How neurons can detect long lasting acid environments remains largely unknown. Although TRPV3 cannot sense the extracellular protons directly, we show in the present study that it can sensitively report intracellular acidification. Because TRPV3 mediates responses to warm temperatures above 33 °C, TRPV3 confers a basal activity at body temperatures that might allow protons to enter the cell and further activate the channel at elevated extracellular proton levels, thus acting as a primary pH sensor. Interestingly, Miyamoto et al. (
      • Miyamoto T.
      • Petrus M.J.
      • Dubin A.E.
      • Patapoutian A.
      TRPV3 regulates nitric-oxide synthase-independent nitric oxide synthesis in the skin.
      ) recently reported that TRPV3 regulates nitric-oxide syntheses in the skin through a pH-dependent fashion. The activation of TRPV1 or other proton-permeable channels that are coexpressed with TRPV3 in many cell types may further facilitate cytosolic acidification (
      • Hellwig N.
      • Plant T.D.
      • Janson W.
      • Schäfer M.
      • Schultz G.
      • Schaefer M.
      TRPV1 acts as proton channel to induce acidification in nociceptive neurons.
      ), supporting a role for TRPV3 in acid sensing, acid-induced pain, and acid-evoked feedback regulation of homeostatic reactions. For these reasons, TRPV3 may be an attractive target for the development of analgesic drugs to relieve acidic pain (
      • Reilly R.M.
      • Kym P.R.
      Analgesic potential of TRPV3 antagonists.
      ).
      An interesting observation of the present study was that increasing the concentration of intracellular protons beyond pH 5.5 evoked little TRPV3 current, but a robust transient response was observed when the acidic solution was replaced. This off-response has been suggested to have a potential association with sour taste sensation in mammals (
      • Xu H.
      • Delling M.
      • Jun J.C.
      • Clapham D.E.
      Oregano, thyme, and clove-derived flavors and skin sensitizers activate specific TRP channels.
      ,
      • Danilova V.
      • Danilov Y.
      • Roberts T.
      • Tinti J.M.
      • Nofre C.
      • Hellekant G.
      Sense of taste in a new world monkey, the common marmoset. Recordings from the chorda tympani and glossopharyngeal nerves.
      ,
      • DeSimone J.A.
      • Callaham E.M.
      • Heck G.L.
      Chorda tympani taste response of rat to hydrochloric acid subject to voltage-clamped lingual receptive field.
      ,
      • Lin W.
      • Ogura T.
      • Kinnamon S.C.
      Acid-activated cation currents in rat vallate taste receptor cells.
      ,
      • Inada H.
      • Kawabata F.
      • Ishimaru Y.
      • Fushiki T.
      • Matsunami H.
      • Tominaga M.
      Off-response property of an acid-activated cation channel complex PKD1L3-PKD2L1.
      ). We showed here that this off-response is predominantly due to the removal of inhibition effects of intracellular protons on single-channel conductance. It reveals that the gating process underlying recovery from low pH-induced activation is quite slow. Our data also suggest that the strong inhibition of the TRPV3 current at highly acidic pH levels may not be accounted for by simple conductance inhibition, indicating that an inhibitory effect of proton on channel gating may also exist. A second pH sensing domain or general charge effects on the TRP domain may contribute to this inhibition (
      • Valente P.
      • Fernández-Carvajal A.
      • Camprubí-Robles M.
      • Gomis A.
      • Quirce S.
      • Viana F.
      • Fernández-Ballester G.
      • González-Ros J.M.
      • Belmonte C.
      • Planells-Cases R.
      • Ferrer-Montiel A.
      Membrane-tethered peptides patterned after the TRP domain (TRPducins) selectively inhibit TRPV1 channel activity.
      ).
      In summary, we have demonstrated that intracellular protons can strongly activate TRPV3, revealing a coupling between cytosolic protons and calcium. When the channel is sensitized, extracellular proton can efficiently pass through the channel pore to further open the channel, so that TRPV3 can detect both intracellular and extracellular acidosis under physiological or pathophysiological conditions. The sensitivity of TRPV3 to acidosis may explain the cosmetic effect of topical AHAs and provide a new target for pain medication and human skin diseases caused by TRPV3 gain-of-function mutations (
      • Lin Z.
      • Chen Q.
      • Lee M.
      • Cao X.
      • Zhang J.
      • Ma D.
      • Chen L.
      • Hu X.
      • Wang H.
      • Wang X.
      • Zhang P.
      • Liu X.
      • Guan L.
      • Tang Y.
      • Yang H.
      • Tu P.
      • Bu D.
      • Zhu X.
      • Wang K.
      • Li R.
      • Yang Y.
      Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome.
      ).

      Acknowledgments

      We thank our laboratory members Yiquan Tang, Jun Su, and Xiling Bian for discussion. We also thank J. M. Wang for consistent support during this research.

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