doi:10.1371/journal.pone.0222619engLozano-Gerona, J.Oliván-Viguera, A.Delgado-Wicke, P.Singh, V.Brown, B.M.Tapia-Casellas, E.Pueyo, E.Valero, M.S.Garcia-Otín, Á.L.Giraldo, P.Abarca-Lachen, E.Surra, J.C.Osada, J.Hamilton, K.L.Raychaudhuri, S.P.Marigil, M.Juarranz, Á.Wulff, H.Miura, H.Gilaberte, Y.Köhler, R.Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosisART-2020-117407Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-ß1 (60-fold), IL-6 (33-fold), and TNFa (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-ß1 (-88%) and IL-6 (-90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles pathological features of eczematous dermatitis and identifies KCa3.1 as a regulator of epidermal homeostasis and spongiosis, and as a potential therapeutic target.2020http://zaguan.unizar.es/record/8961410.1371/journal.pone.0222619http://zaguan.unizar.es/record/89614oai:zaguan.unizar.es:89614info:eu-repo/grantAgreement/ES/DGA/B04-17Rinfo:eu-repo/grantAgreement/ES/DGA-FEDER/T39-17R-BSICoSinfo:eu-repo/grantAgreement/EUR/FP7/PEOPLE-MC-CIGinfo:eu-repo/grantAgreement/EC/H2020/638284/EU/Is your heart aging well? A systems biology approach to characterize cardiac aging from the cell to the body surface/MODELAGEThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 638284-MODELAGEinfo:eu-repo/grantAgreement/ES/ISCIII/FIS-CB06-07-1036info:eu-repo/grantAgreement/ES/ISCIII/FIS-PI16-02112info:eu-repo/grantAgreement/ES/MINECO/DPI2016-75458-RPloS one 15, 3 (2020), e0222619 [18 pp.]byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess