title: 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.
authors.affiliation: From the Departments of Neurology, yong.chen@duke.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Departments of Neurology.
authors.forename: Quan
authors.initials: Q
authors.lastname: Fang
authors.affiliation: From the Departments of Neurology.
authors.forename: Zilong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Dermatology.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: Dermatology.
authors.forename: Amanda S
authors.initials: AS
authors.lastname: MacLeod
authors.affiliation: Dermatology.
authors.forename: Russell P
authors.initials: RP
authors.lastname: Hall
authors.affiliation: From the Departments of Neurology, Neurobiology, and Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710 and Neurology Clinics for Headache, Head Pain and Trigeminal Sensory Disorders, Duke University Medical Center, Durham, North Carolina 27705 wolfgang@neuro.duke.edu.
authors.forename: Wolfgang B
authors.initials: WB
authors.lastname: Liedtke
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006632:Histamine / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D011537:Pruritus / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D019332:Endothelin-1; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D006632:Histamine
keywords: TRPV4; calcium; extracellular-signal-regulated kinase (ERK); histaminergic itch; inhibitor; keratinocyte; pruritogen; skin