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Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels

Academic Article
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Overview

authors

  • Xiao, B.
  • Dubin, Adrienne
  • Bursulaya, B.
  • Viswanath, V.
  • Jegla, T. J.
  • Patapoutian, Ardem

publication date

  • September 2008

journal

  • Journal of Neuroscience  Journal

abstract

  • TRPA1 is a member of the transient receptor potential (TRP) family of ion channels and is expressed in a subset of nociceptive neurons. An increasing body of evidence suggests that TRPA1 functions as a chemical nocisensor for a variety of reactive chemicals, such as pungent natural compounds and environmental irritants. Activation of TRPA1 by reactive compounds has been demonstrated to be mediated through covalent modification of cytoplasmic cysteines located in the N terminus of the channel, rather than classical lock-and-key binding. TRPA1 activity is also modulated by numerous nonreactive chemicals, but the underlying mechanism is unknown. Menthol, a natural nonreactive cooling compound, is best known as an activator of TRPM8, a related TRP ion channel required for cool thermosensation in vivo. More recently, menthol has been shown to be an activator of mouse TRPA1 at low concentrations, and a blocker, at high concentrations. Here, we show that human TRPA1 is only activated by menthol, whereas TRPA1 from nonmammalian species are insensitive to menthol. Mouse-human TRPA1 chimeras reveal the pore region [including transmembrane domain 5 (TM5) and TM6] as the critical domain determining whether menthol can act as an inhibitor. Furthermore, chimeras between Drosophila melanogaster and mammalian TRPA1 highlight specific residues within TM5 critical for menthol responsiveness. Interestingly, this TM5 region also determines the sensitivity of TRPA1 to other chemical modulators. These data suggest separable structural requirements for modulation of TRPA1 by covalent and nonreactive molecules. Whether this region is involved in binding or gating of TRPA1 channels is discussed.

subject areas

  • Animals
  • Antipruritics
  • Bacterial Proteins
  • Benzamides
  • Cell Line, Transformed
  • Cloning, Molecular
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Drosophila Proteins
  • Drosophila melanogaster
  • Electric Stimulation
  • HSP90 Heat-Shock Proteins
  • Humans
  • Luminescent Proteins
  • Membrane Potentials
  • Menthol
  • Mutagenesis
  • Patch-Clamp Techniques
  • Protein Structure, Tertiary
  • Thymol
  • Transfection
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Research

keywords

  • TRPA1
  • binding pocket
  • chemical nocisensor
  • menthol
  • nociception
  • transient receptor potential
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Identity

PubMed Central ID

  • PMC2678945

International Standard Serial Number (ISSN)

  • 0270-6474

Digital Object Identifier (DOI)

  • 10.1523/jneurosci.2772-08.2008

PubMed ID

  • 18815250
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Additional Document Info

start page

  • 9640

end page

  • 9651

volume

  • 28

issue

  • 39

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