Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.
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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.
extracellular-signal-regulated kinase (ERK)
Gene Expression Regulation
MAP Kinase Signaling System
TRPV Cation Channels
Published Version (Please cite this version)10.1074/jbc.M116.716464
Publication InfoChen, 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.
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Assistant Professor in Neurology
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
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.
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
Associate 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
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