Specific TRPC6 channel activation, a novel approach to stimulate keratinocyte differentiation

Muller, Margarethe; Essin, Kirill; Hill, Kerstin; Beschmann, Heike; Rubant, Simone A.; Schempp, Christoph M.; Gollasch, Maik; Boehncke, Wolf-Henning; Harteneck, Christian; Muller, Walter E.; Leuner, Kristina

doi:10.1074/jbc.M801844200

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Title		Specific TRPC6 channel activation, a novel approach to stimulate keratinocyte differentiation
Authors		Muller, Margarethe Essin, Kirill Hill, Kerstin Beschmann, Heike Rubant, Simone A. Schempp, Christoph M. Gollasch, Maik Boehncke, Wolf-Henning Harteneck, Christian Muller, Walter E. Leuner, Kristina show all authors [1 - 11]
Published in		Journal of Biological Chemistry. 2008, vol. 283, no. 49, p. 33942-33954
Abstract		The protective epithelial barrier in our skin undergoes constant regulation, whereby the balance between differentiation and proliferation of keratinocytes plays a major role. Impaired keratinocyte differentiation and proliferation are key elements in the pathophysiology of several important dermatological diseases, including atopic dermatitis and psoriasis. Ca(2+) influx plays an essential role in this process presumably mediated by different transient receptor potential (TRP) channels. However, investigating their individual role was hampered by the lack of specific stimulators or inhibitors. Because we have recently identified hyperforin as a specific TRPC6 activator, we investigated the contribution of TRPC6 to keratinocyte differentiation and proliferation. Like the endogenous differentiation stimulus high extracellular Ca(2+) concentration ([Ca(2+)](o)), hyperforin triggers differentiation in HaCaT cells and in primary cultures of human keratinocytes by inducing Ca(2+) influx via TRPC6 channels and additional inhibition of proliferation. Knocking down TRPC6 channels prevents the induction of Ca(2+)- and hyperforin-induced differentiation. Importantly, TRPC6 activation is sufficient to induce keratinocyte differentiation similar to the physiological stimulus [Ca(2+)](o). Therefore, TRPC6 activation by hyperforin may represent a new innovative therapeutic strategy in skin disorders characterized by altered keratinocyte differentiation.
Keywords		Bicyclo Compounds/pharmacology — Calcium/chemistry — Cations — Cell Differentiation — Cell Line, Tumor — Cell Proliferation — Humans — Keratinocytes/cytology/metabolism — Models, Biological — Organ Culture Techniques/methods — Phloroglucinol/analogs & derivatives/pharmacology — Skin/metabolism — Skin Diseases/metabolism — TRPC Cation Channels/chemistry/physiology — Terpenes/pharmacology — Time Factors — Transfection
Identifiers		DOI: 10.1074/jbc.M801844200 PMID: 18818211
Full text		Article - Limited access to UNIGE Other version: http://www.jbc.org/content/283/49/33942.full.pdf
Citation (ISO format)		MULLER, Margarethe et al. Specific TRPC6 channel activation, a novel approach to stimulate keratinocyte differentiation. In: Journal of Biological Chemistry, 2008, vol. 283, n° 49, p. 33942-33954. doi: 10.1074/jbc.M801844200 https://archive-ouverte.unige.ch/unige:29772