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Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.

Publication ,  Journal Article
Chen, Y; Fang, Q; Wang, Z; Zhang, JY; MacLeod, AS; Hall, RP; Liedtke, WB
Published in: J Biol Chem
May 6, 2016

TRPV4 ion channels function in epidermal keratinocytes and in innervating sensory neurons; however, the contribution of the channel in either cell to neurosensory function remains to be elucidated. We recently reported TRPV4 as a critical component of the keratinocyte machinery that responds to ultraviolet B (UVB) and functions critically to convert the keratinocyte into a pain-generator cell after excess UVB exposure. One key mechanism in keratinocytes was increased expression and secretion of endothelin-1, which is also a known pruritogen. Here we address the question of whether TRPV4 in skin keratinocytes functions in itch, as a particular form of "forefront" signaling in non-neural cells. Our results support this novel concept based on attenuated scratching behavior in response to histaminergic (histamine, compound 48/80, endothelin-1), not non-histaminergic (chloroquine) pruritogens in Trpv4 keratinocyte-specific and inducible knock-out mice. We demonstrate that keratinocytes rely on TRPV4 for calcium influx in response to histaminergic pruritogens. TRPV4 activation in keratinocytes evokes phosphorylation of mitogen-activated protein kinase, ERK, for histaminergic pruritogens. This finding is relevant because we observed robust anti-pruritic effects with topical applications of selective inhibitors for TRPV4 and also for MEK, the kinase upstream of ERK, suggesting that calcium influx via TRPV4 in keratinocytes leads to ERK-phosphorylation, which in turn rapidly converts the keratinocyte into an organismal itch-generator cell. In support of this concept we found that scratching behavior, evoked by direct intradermal activation of TRPV4, was critically dependent on TRPV4 expression in keratinocytes. Thus, TRPV4 functions as a pruriceptor-TRP in skin keratinocytes in histaminergic itch, a novel basic concept with translational-medical relevance.

Duke Scholars

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

May 6, 2016

Volume

291

Issue

19

Start / End Page

10252 / 10262

Location

United States

Related Subject Headings

  • Ultraviolet Rays
  • TRPV Cation Channels
  • Pruritus
  • Organ Specificity
  • Mice, Knockout
  • Mice
  • MAP Kinase Signaling System
  • Keratinocytes
  • Histamine
  • Gene Expression Regulation
 

Citation

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Chen, Y., Fang, Q., Wang, Z., Zhang, J. Y., MacLeod, A. S., Hall, R. P., & Liedtke, W. B. (2016). Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch. J Biol Chem, 291(19), 10252–10262. https://doi.org/10.1074/jbc.M116.716464
Chen, Yong, Quan Fang, Zilong Wang, Jennifer Y. Zhang, Amanda S. MacLeod, Russell P. Hall, and Wolfgang B. Liedtke. “Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.J Biol Chem 291, no. 19 (May 6, 2016): 10252–62. https://doi.org/10.1074/jbc.M116.716464.
Chen Y, Fang Q, Wang Z, Zhang JY, MacLeod AS, Hall RP, et al. Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch. J Biol Chem. 2016 May 6;291(19):10252–62.
Chen, Yong, et al. “Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.J Biol Chem, vol. 291, no. 19, May 2016, pp. 10252–62. Pubmed, doi:10.1074/jbc.M116.716464.
Chen Y, Fang Q, Wang Z, Zhang JY, MacLeod AS, Hall RP, Liedtke WB. Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch. J Biol Chem. 2016 May 6;291(19):10252–10262.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

May 6, 2016

Volume

291

Issue

19

Start / End Page

10252 / 10262

Location

United States

Related Subject Headings

  • Ultraviolet Rays
  • TRPV Cation Channels
  • Pruritus
  • Organ Specificity
  • Mice, Knockout
  • Mice
  • MAP Kinase Signaling System
  • Keratinocytes
  • Histamine
  • Gene Expression Regulation