Cited by 141Ion Channels and ReceptorsCalcium signaling and nucleotide metabolismNitric Oxide and Endothelin Effects

TRPV3 regulates nitric oxide synthase-independent nitric oxide synthesis in the skin

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Miyamoto, Takashi, Petrus, Matt J., Dubin, Adrienne E., Patapoutian, Ardem·2011·Nature Communications

Abstract

Nitric oxide (NO) is an unstable signalling molecule synthesized de novo mainly from L-arginine by NO synthase (NOS) enzymes. Nitrite reduction can also produce NO, predominantly within body fluids (for example, saliva, sweat and blood plasma) and under extreme hypoxic and acidic conditions. It remains unknown if intracellular canonical signalling pathways regulate nitrite-dependent NO production. Here we examine NO production in the skin, a hypoxic tissue enriched in nitrites wherein NO has important roles in wound healing and other biological processes. We show that activation of TRPV3, a heat-activated transient receptor potential ion channel expressed in keratinocytes, induces NO production via a nitrite-dependent pathway. TRPV3 and nitrite are involved in keratinocyte migration in vitro and in wound healing and thermosensory behaviours in vivo. Our study demonstrates that activation of an ion channel can induce NOS-independent NO production in keratinocytes.

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  • Activation of the TRPV3 channel in the skin can stimulate NO formation independently of NOS, linking nitrite-derived NO to thermoregulation and cutaneous blood flow.

    “For instance, activation of the transient receptor potential vanilloid 3 (TRPV3) channel in the skin can stimulate NO formation independently of NOS, thereby linking nitrite-derived NO to thermoregulation and cutaneous blood flow [39].”

    From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [39]

    The Abstract (page unavailable) reports that TRPV3 activation induces nitrite-dependent, NOS-independent NO production in skin keratinocytes. The Results and Discussion link TRPV3 and nitrite to thermosensory behavior, but do not establish a role in thermoregulation or cutaneous blood flow; the Discussion says only that nitrite-dependent NO could participate in heat-induced vasodilation. (LLM, conf=0.87)

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Research works printed but not linked: 52

  1. [1]MacMicking J Xie QW Nathan C Nitric oxide and macrophage function Annu Rev Immunol 15 323 350 10.1146/annurev.immunol.15.1.323 1997 9143691 · DOI
  2. [2]Bredt DS Snyder SH Nitric oxide: a physiologic messenger molecule Annu Rev Biochem 63 175 195 10.1146/annurev.bi.63.070194.001135 1994 7526779 · DOI
  3. [3]Ignarro LJ Endothelium-derived nitric oxide: actions and properties FASEB J 3 31 36 1989 2642868
  4. [4]Chvanov M Gerasimenko OV Petersen OH Tepikin AV Calcium-dependent release of NO from intracellular S-nitrosothiols EMBO J 25 3024 3032 7601207 [pii] 10.1038/sj.emboj.7601207 2006 16810320 PMC1500983 · DOI
  5. [5]Furchgott RF Ehrreich SJ Greenblatt E The photoactivated relaxation of smooth muscle of rabbit aorta J Gen Physiol 44 499 519 1961 13702637 PMC2195116
  6. [7]Suschek CV Schewe T Sies H Kroncke KD Nitrite, a naturally occurring precursor of nitric oxide that acts like a ‘prodrug’ Biol Chem 387 499 506 10.1515/BC.2006.065 2006 16740120 · DOI
  7. [9]Zweier JL Wang P Samouilov A Kuppusamy P Enzyme-independent formation of nitric oxide in biological tissues Nat Med 1 804 809 1995 7585184
  8. [10]Zhang Z Human xanthine oxidase converts nitrite ions into nitric oxide (NO) Biochem Soc Trans 25 524S 1997 9388740
  9. [13]Lundberg JO Weitzberg E Lundberg JM Alving K Intragastric nitric oxide production in humans: measurements in expelled air Gut 35 1543 1546 1994 7828969 PMC1375608
  10. [14]Weller R Nitric oxide is generated on the skin surface by reduction of sweat nitrate J Invest Dermatol 107 327 331 1996 8751965
  11. [15]Paunel AN Enzyme-independent nitric oxide formation during UVA challenge of human skin: characterization, molecular sources, and mechanisms Free Radic Biol Med 38 606 615 S0891-5849(04)00923-2 [pii] 10.1016/j.freeradbiomed.2004.11.018 2005 15683717 · DOI · Paper page
  12. [16]Cals-Grierson MM Ormerod AD Nitric oxide function in the skin Nitric Oxide 10 179 193 10.1016/j.niox.2004.04.005 S1089860304000734 [pii] 2004 15275864 · DOI
  13. [17]Kellogg DL Jr Crandall CG Liu Y Charkoudian N Johnson JM Nitric oxide and cutaneous active vasodilation during heat stress in humans J Appl Physiol 85 824 829 1998 9729553
  14. [18]Peier AM A heat-sensitive TRP channel expressed in keratinocytes Science 296 2046 2049 10.1126/science.1073140 1073140 [pii] 2002 12016205 · DOI
  15. [19]Moqrich A Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin Science 307 1468 1472 307/5714/1468 [pii] 10.1126/science.1108609 2005 15746429 · DOI
  16. [20]Cheng X TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation Cell 141 331 343 S0092-8674(10)00286-2 [pii] 10.1016/j.cell.2010.03.013 2010 20403327 PMC2858065 · DOI
  17. [21]McQuade LE Lippard SJ Fluorescent probes to investigate nitric oxide and other reactive nitrogen species in biology (truncated form: fluorescent probes of reactive nitrogen species) Curr Opin Chem Biol 14 43 49 S1367-5931(09)00150-1 [pii] 10.1016/j.cbpa.2009.10.004 2010 19926519 · DOI
  18. [22]Chung MK Lee H Mizuno A Suzuki M Caterina MJ 2-aminoethoxydiphenyl borate activates and sensitizes the heat-gated ion channel TRPV3 J Neurosci 24 5177 5182 10.1523/JNEUROSCI.0934-04.2004 24/22/5177 [pii] 2004 15175387 PMC6729202 · DOI
  19. [23]Hu HZ 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3 J Biol Chem 279 35741 35748 10.1074/jbc.M404164200 M404164200 [pii] 2004 15194687 · DOI
  20. [24]Mathews WR Kerr SW Biological activity of S-nitrosothiols: the role of nitric oxide J Pharmacol Exp Ther 267 1529 1537 1993 7903392
  21. [25]Son H Long-term potentiation is reduced in mice that are doubly mutant in endothelial and neuronal nitric oxide synthase Cell 87 1015 1023 S0092-8674(00)81796-1 [pii] 1996 8978606
  22. [26]Evans SM Schrlau AE Chalian AA Zhang P Koch CJ Oxygen levels in normal and previously irradiated human skin as assessed by EF5 binding J Invest Dermatol 126 2596 2606 5700451 [pii] 10.1038/sj.jid.5700451 2006 16810299 · DOI · Paper page
  23. [27]Granger DL Hibbs JB Jr Broadnax LM Urinary nitrate excretion in relation to murine macrophage activation. Influence of dietary L-arginine and oral NG-monomethyl-L-arginine J Immunol 146 1294 1302 1991 1991968
  24. [28]Li H Cui H Kundu TK Alzawahra W Zweier JL Nitric oxide production from nitrite occurs primarily in tissues not in the blood: critical role of xanthine oxidase and aldehyde oxidase J Biol Chem 283 17855 17863 M801785200 [pii] 10.1074/jbc.M801785200 2008 18424432 PMC2440597 · DOI · Paper page
  25. [29]Roos A Boron WF Intracellular pH Physiol Rev 61 296 434 1981 7012859
  26. [30]Chung MK Lee H Mizuno A Suzuki M Caterina MJ TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes J Biol Chem 279 21569 21575 10.1074/jbc.M401872200 M401872200 [pii] 2004 15004014 · DOI
  27. [31]Miesenbock G De Angelis DA Rothman JE Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins Nature 394 192 195 10.1038/28190 1998 9671304 · DOI
  28. [32]Hellwig N TRPV1 acts as proton channel to induce acidification in nociceptive neurons J Biol Chem 279 34553 34561 10.1074/jbc.M402966200 M402966200 [pii] 2004 15173182 · DOI
  29. [33]Chung MK Guler AD Caterina MJ Biphasic currents evoked by chemical or thermal activation of the heat-gated ion channel, TRPV3 J Biol Chem 280 15928 15941 M500596200 [pii] 10.1074/jbc.M500596200 2005 15722340 · DOI
  30. [34]Grandl J Pore region of TRPV3 ion channel is specifically required for heat activation Nat Neurosci 11 1007 1013 2008 19160498 PMC2685190
  31. [35]Dhaka A Viswanath V Patapoutian A Trp ion channels and temperature sensation Annu Rev Neurosci 29 135 161 10.1146/annurev.neuro.29.051605.112958 2006 16776582 · DOI · Paper page
  32. [36]Caterina MJ Impaired nociception and pain sensation in mice lacking the capsaicin receptor Science 288 306 313 8443 [pii] 2000 10764638
  33. [37]Gavva NR Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade J Pharmacol Exp Ther 323 128 137 jpet.107.125674 [pii] 10.1124/jpet.107.125674 2007 17652633 · DOI · Paper page
  34. [38]Miyamoto T Dubin AE Petrus MJ Patapoutian A TRPV1 and TRPA1 mediate peripheral nitric oxide-induced nociception in mice PLoS One 4 e7596 10.1371/journal.pone.0007596 2009 19893614 PMC2764051 · DOI
  35. [39]Story GM ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures Cell 112 819 829 S0092867403001582 [pii] 2003 12654248
  36. [40]McNamara CR TRPA1 mediates formalin-induced pain Proc Natl Acad Sci U S A 104 13525 13530 0705924104 [pii] 10.1073/pnas.0705924104 2007 17686976 PMC1941642 · DOI
  37. [41]Sokabe T Fukumi-Tominaga T Yonemura S Mizuno A Tominaga M The TRPV4 channel contributes to intercellular junction formation in keratinocytes J Biol Chem 285 18749 18758 M110.103606 [pii] 10.1074/jbc.M110.103606 2010 20413591 PMC2881798 · DOI · Paper page
  38. [42]Rizk M Witte MB Barbul A Nitric oxide and wound healing World J Surg 28 301 306 10.1007/s00268-003-7396-7 2004 14961192 · DOI
  39. [43]Yamada T Functional expression of transient receptor potential vanilloid 3 (TRPV3) in corneal epithelial cells: involvement in thermosensation and wound healing Exp Eye Res 90 121 129 S0014-4835(09)00288-7 [pii] 10.1016/j.exer.2009.09.020 2010 19793539 · DOI
  40. [44]Kirfel G Herzog V Migration of epidermal keratinocytes: mechanisms, regulation, and biological significance Protoplasma 223 67 78 10.1007/s00709-003-0031-5 2004 15221512 · DOI
  41. [45]Tkalcevic VI Cuzic S Parnham MJ Pasalic I Brajsa K Differential evaluation of excisional non-occluded wound healing in db/db mice Toxicol Pathol 37 183 192 0192623308329280 [pii] 10.1177/0192623308329280 2009 19182213 · DOI
  42. [46]Lundberg JO Weitzberg E NO-synthase independent NO generation in mammals Biochem Biophys Res Commun 396 39 45 S0006-291X(10)00370-0 [pii] 10.1016/j.bbrc.2010.02.136 2010 20494108 · DOI
  43. [48]Denda M Immunoreactivity of VR1 on epidermal keratinocyte of human skin Biochem Biophys Res Commun 285 1250 1252 10.1006/bbrc.2001.5299 S0006-291X(01)95299-4 [pii] 2001 11478791 · DOI
  44. [49]Kwan KY Glazer JM Corey DP Rice FL Stucky CL TRPA1 modulates mechanotransduction in cutaneous sensory neurons J Neurosci 29 4808 4819 29/15/4808 [pii] 10.1523/JNEUROSCI.5380-08.2009 2009 19369549 PMC2744291 · DOI
  45. [50]Huang SM Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2 J Neurosci 28 13727 13737 28/51/13727 [pii] 10.1523/JNEUROSCI.5741-07.2008 2008 19091963 PMC2676929 · DOI
  46. [51]Mandadi S TRPV3 in keratinocytes transmits temperature information to sensory neurons via ATP Pflugers Arch 458 1093 1102 10.1007/s00424-009-0703-x 2009 19669158 PMC2745623 · DOI
  47. [52]Xu H Delling M Jun JC Clapham DE Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels Nat Neurosci 9 628 635 nn1692 [pii] 10.1038/nn1692 2006 16617338 · DOI
  48. [54]Basbaum AI Bautista DM Scherrer G Julius D Cellular and molecular mechanisms of pain Cell 139 267 284 S0092-8674(09)01243-4 [pii] 10.1016/j.cell.2009.09.028 2009 19837031 PMC2852643 · DOI · Paper page
  49. [55]Lee H Iida T Mizuno A Suzuki M Caterina MJ Altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4 J Neurosci 25 1304 1310 25/5/1304 [pii] 10.1523/JNEUROSCI.4745.04.2005 2005 15689568 PMC6725965 · DOI
  50. [56]Birder LA Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1 Nat Neurosci 5 856 860 10.1038/nn902 nn902 [pii] 2002 12161756 · DOI
  51. [57]Yang D Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension Cell Metab 12 130 141 S1550-4131(10)00228-7 [pii] 10.1016/j.cmet.2010.05.015 2010 20674858 PMC3906919 · DOI
  52. [58]Marsch R Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice J Neurosci 27 832 839 27/4/832 [pii] 10.1523/JNEUROSCI.3303–06.2007 2007 17251423 PMC6672910 · DOI · Paper page

Cited by

Sorted by citations

Authors
Miyamoto, T., Petrus, M. J., Dubin, A. E., & Patapoutian, A.
Affiliations
  • Scripps Research Institute (US)
  • Genomics Institute of the Novartis Research Foundation (US)
Corresponding author
Patapoutian, Ardem
Venue
Nature Communications
Published
2011-06-28
Volume
2
Issue
1
Pages
369-369
ISSN
2041-1723 (ISSN-L)
OpenAlex
W1966176614
Cited by
141
References
7
Citations by year
2026: 4 · 2025: 13 · 2024: 9 · 2023: 11 · 2022: 13 · 2021: 11 · 2020: 8 · 2019: 5 · 2018: 6 · 2017: 7 · 2016: 7 · 2015: 15 · 2014: 13 · 2013: 10 · 2012: 8
FWCI
5.52
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Thailand Science Research and Innovation
  • National Institute of Neurological Disorders and Stroke (R01NS046303)
  • National Institute of Dental and Craniofacial Research (R21DE021181)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
TRPV3, nitric oxide, nitrite reduction, keratinocytes, skin, wound healing, ion channel activation, hypoxia, keratinocyte migration
MeSH terms
Analysis of Variance, Animals, Animals, Newborn, Cells, Cultured, Nitric Oxide, Nitrites, Wound Healing, Keratinocytes, Polymerase Chain Reaction, DNA Primers, Electroporation, Cell Proliferation, TRPV Cation Channels, Mice

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