title: Reversal of murine epidermal atrophy by topical modulation of calcium signaling.
abstract: Cytosolic Ca(2+) signals are performed by Ca(2+) releases from the endoplasmic reticulum and Ca(2+) influx from the extracellular medium. Releases rely on the refilling of the intracellular Ca(2+) stores by the Ca(2+) influx "Store-Operated Calcium Entry" (SOCE) via the channel Orai1. Here we show that Orai1 expression, SOCE amplitude, and epidermal proliferation are decreased in the epidermis of patients with skin fragility when compared with aged nonatrophic skin. Epidermal atrophy was induced in mice by the inhibition of Orai1 with small interfering RNA and the topical application of a SOCE blocker BTP2. The inhibition of Orai1 impaired the heparin-binding epidermal growth factor (HB-EGF)-induced Ca(2+) influxes and fully prevented the mitogen effect of HB-EGF in primary human keratinocytes. Importantly, epidermal proliferation correlated with Orai1 expression in mice. Conversely, the topical application of an Orai1 activator, the benzohydroquinone (BHQ), increased the epidermal thickness and proliferation, whereas the pro-proliferative effect of BHQ was prevented by the inhibition of Orai1. Finally, the topical application of BHQ reversed the epidermal atrophy induced by corticosteroids in mice. The topical modulation of Ca(2+) signals may thus be a promising therapeutic strategy in dermatology.
authors: Department of Dermatology, University Hospital of Geneva, Geneva, Switzerland. Electronic address: Basile.darbellay@unige.ch.
authors: Basile
authors: B
authors: Darbellay
authors: Department of Dermatology, University Hospital of Geneva, Geneva, Switzerland.
authors: Laurent
authors: L
authors: Barnes
authors: Department of Dermatology, University Hospital of Geneva, Geneva, Switzerland.
authors: Wolf-Henning
authors: WH
authors: Boehncke
authors: Swiss Center for Applied Human Toxicology, University of Geneva, Geneva, Switzerland.
authors: Jean-Hilaire
authors: JH
authors: Saurat
authors: Department of Dermatology, University Hospital of Geneva, Geneva, Switzerland.
authors: Gürkan
authors: G
authors: Kaya
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001284:Atrophy / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D049109:Cell Proliferation; D003600:Cytosol / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D008345:Manganese / Q000494:pharmacology; D051379:Mice; D000071740:ORAI1 Protein; D034741:RNA, Small Interfering / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D015220:Calcium Channels; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D006873:Hydroquinones; D036341:Intercellular Signaling Peptides and Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C520430:Orai1 protein, mouse; D034741:RNA, Small Interfering; D013830:Thiadiazoles; D008345:Manganese; D002118:Calcium