title: Reduced TRPC channel expression in psoriatic keratinocytes is associated with impaired differentiation and enhanced proliferation.
abstract: Psoriasis is a characteristic inflammatory and scaly skin condition with typical histopathological features including increased proliferation and hampered differentiation of keratinocytes. The activation of innate and adaptive inflammatory cellular immune responses is considered to be the main trigger factor of the epidermal changes in psoriatic skin. However, the molecular players that are involved in enhanced proliferation and impaired differentiation of psoriatic keratinocytes are only partly understood. One important factor that regulates differentiation on the cellular level is Ca(2+). In normal epidermis, a Ca(2+) gradient exists that is disturbed in psoriatic plaques, favoring impaired keratinocyte proliferation. Several TRPC channels such as TRPC1, TRPC4, or TRPC6 are key proteins in the regulation of high [Ca(2+)](ex) induced differentiation. Here, we investigated if TRPC channel function is impaired in psoriasis using calcium imaging, RT-PCR, western blot analysis and immunohistochemical staining of skin biopsies. We demonstrated substantial defects in Ca(2+) influx in psoriatic keratinocytes in response to high extracellular Ca(2+) levels, associated with a downregulation of all TRPC channels investigated, including TRPC6 channels. As TRPC6 channel activation can partially overcome this Ca(2+) entry defect, specific TRPC channel activators may be potential new drug candidates for the topical treatment of psoriasis.
authors.affiliation: Institute of Pharmacology, Biocenter Niederursel, Johann Wolfgang Goethe-University, Frankfurt, Germany. Leuner@em.uni-frankfurt.de
authors.forename: Kristina
authors.initials: K
authors.lastname: Leuner
authors.forename: Margarethe
authors.initials: M
authors.lastname: Kraus
authors.forename: Ute
authors.initials: U
authors.lastname: Woelfle
authors.forename: Heike
authors.initials: H
authors.lastname: Beschmann
authors.forename: Christian
authors.initials: C
authors.lastname: Harteneck
authors.forename: Wolf-Henning
authors.initials: WH
authors.lastname: Boehncke
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Schempp
authors.forename: Walter E
authors.initials: WE
authors.lastname: Müller
mesh_terms: D000328:Adult; D000368:Aged; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D050052:TRPC Cation Channels / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D050052:TRPC Cation Channels