Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.
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.
Type
Journal articleSubject
TRPV4calcium
extracellular-signal-regulated kinase (ERK)
histaminergic itch
inhibitor
keratinocyte
pruritogen
skin
Animals
Calcium Signaling
Endothelin-1
Epidermis
Gene Expression Regulation
Histamine
Keratinocytes
MAP Kinase Signaling System
Mice
Mice, Knockout
Organ Specificity
Pruritus
TRPV Cation Channels
Ultraviolet Rays
Permalink
https://hdl.handle.net/10161/12969Published Version (Please cite this version)
10.1074/jbc.M116.716464Publication Info
Chen, Yong; Fang, Quan; Wang, Zilong; Zhang, Jennifer Y; MacLeod, Amanda S; Hall,
Russell P; & Liedtke, Wolfgang 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). pp. 10252-10262. 10.1074/jbc.M116.716464. Retrieved from https://hdl.handle.net/10161/12969.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
Yong Chen
Associate Professor in Neurology
Russell P. Hall III
J. Lamar Callaway Distinguished Professor of Dermatology, in the School of Medicine
Our laboratory is investigating the pathogenesis of autoimmune blistering skin diseases.
Areas of special expertise include immune mediated skin diseases, especially immune
mediated primary blistering disorders. These include pathogenesis, diagnosis, and
management. Specifically our laboratory is investigating the role of the mucosal immune
response in the pathogenesis of dermatitis herpetiformis (DH) and the role the associated
gluten sensitive enteropathy (GSE) plays in the development o
Wolfgang Bernhard Liedtke
Adjunct Professor in the Department of Neurology
Research Interests in the Liedtke-Lab:
Pain/ nociception
Sensory transduction and -transmission
TRP ion channels
Water and salt equilibrium regulated by the central nervous system
Visit the lab's website, download papers and read Dr. Liedtke's CV here.
Amanda S MacLeod
Adjunct Associate Professor in the Department of Dermatology
The MacLeod Lab investigates the dynamic regulation of innate immunity, with specific
focus on host-microbial interactions, antimicrobial host defense, antiviral proteins,
and repair functions.
Skin is an active immune organ and comprises not only epithelial keratinocytes, but
also harbors dendritic cells, macrophages, nerve cells, and other immune cells. Furthermore,
the skin is inhabited by a multitude of microbes, including bacteria, viruses and
fungi and even parasites. The health
Jennifer Yunyan Zhang
Professor in Dermatology
Epidermis of the skin constitutes the largest organ and the outer most barrier of
the body. It is one of the few organs that undergo lifelong self-renewal through a
tight balance of cell growth, differentiation, and programmed cell death. Deregulation
of this balance is manifested in many diseases, including various immune diseases
and cancer.
Our lab is focused on 3 interrelated topics:
1. Gene regulation of epithelial cell proliferation and differenti
Alphabetical list of authors with Scholars@Duke profiles.

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info