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

dc.contributor.author

Chen, Yong

dc.contributor.author

Fang, Quan

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Wang, Zilong

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Zhang, Jennifer Y

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MacLeod, Amanda S

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Hall, Russell P

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Liedtke, Wolfgang B

dc.coverage.spatial

United States

dc.date.accessioned

2016-10-21T02:51:16Z

dc.date.issued

2016-05-06

dc.description.abstract

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.

dc.identifier

http://www.ncbi.nlm.nih.gov/pubmed/26961876

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M116.716464

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1083-351X

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https://hdl.handle.net/10161/12969

dc.language

eng

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Elsevier BV

dc.relation.ispartof

J Biol Chem

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10.1074/jbc.M116.716464

dc.subject

TRPV4

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calcium

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extracellular-signal-regulated kinase (ERK)

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histaminergic itch

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inhibitor

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keratinocyte

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pruritogen

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skin

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Animals

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Calcium Signaling

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Endothelin-1

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Epidermis

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Gene Expression Regulation

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Histamine

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Keratinocytes

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MAP Kinase Signaling System

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Mice

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Mice, Knockout

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Organ Specificity

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Pruritus

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TRPV Cation Channels

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Ultraviolet Rays

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Zhang, Jennifer Y|0000-0002-4485-1750

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Hall, Russell P|0000-0001-7621-4935

duke.contributor.orcid

Liedtke, Wolfgang B|0000-0003-4166-5394

pubs.author-url

http://www.ncbi.nlm.nih.gov/pubmed/26961876

pubs.begin-page

10252

pubs.end-page

10262

pubs.issue

19

pubs.organisational-group

Anesthesiology

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Basic Science Departments

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Clinical Science Departments

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Dermatology

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Duke

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Duke Cancer Institute

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Duke Institute for Brain Sciences

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Immunology

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Institutes and Centers

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Institutes and Provost's Academic Units

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Neurobiology

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Neurology

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Neurology, Headache and Pain

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Pathology

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School of Medicine

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University Institutes and Centers

pubs.publication-status

Published

pubs.volume

291

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