title: Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2.
abstract: The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared with wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E(2) (PGE(2)) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naive mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-17203212 [corrected], however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE(2).
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21025, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Huang
authors.forename: Hyosang
authors.initials: H
authors.lastname: Lee
authors.forename: Man-Kyo
authors.initials: MK
authors.lastname: Chung
authors.forename: Una
authors.initials: U
authors.lastname: Park
authors.forename: Yin Yin
authors.initials: YY
authors.lastname: Yu
authors.forename: Heather B
authors.initials: HB
authors.lastname: Bradshaw
authors.forename: Pierre A
authors.initials: PA
authors.lastname: Coulombe
authors.forename: J Michael
authors.initials: JM
authors.lastname: Walker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caterina
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010146:Pain / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000166:cytology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013696:Temperature; D019076:Transgenes
chemical_list: C500065:4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide; D000631:Aminopyridines; D016861:Cyclooxygenase Inhibitors; D008164:Luminescent Proteins; D010879:Piperazines; D011993:Recombinant Fusion Proteins; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C486760:Trpv3 protein, mouse; D015232:Dinoprostone; D007052:Ibuprofen