Specific TRPC6 channel activation, a novel approach to stimulate keratinocyte differentiation.
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.
Müller
Margarethe
M
Institute of Pharmacology, Biocenter Niederursel, Johann Wolfgang Goethe-University, Max-von-Laue-Strasse 9, 60439 Frankfurt, Germany.
Essin
Kirill
K
Hill
Kerstin
K
Beschmann
Heike
H
Rubant
Simone
S
Schempp
Christoph M
CM
Gollasch
Maik
M
Boehncke
W Henning
WH
Harteneck
Christian
C
Müller
Walter E
WE
Leuner
Kristina
K
D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry; D002412:Cations; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D008954:Models, Biological; D009924:Organ Culture Techniques / Q000379:methods; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D012867:Skin / Q000378:metabolism; D012871:Skin Diseases / Q000378:metabolism; D050052:TRPC Cation Channels / Q000737:chemistry / Q000502:physiology*; D000074287:TRPC6 Cation Channel; D013729:Terpenes / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection
D001643:Bridged Bicyclo Compounds; D002412:Cations; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D013729:Terpenes; D010696:Phloroglucinol; C001654:hyperforin; D002118:Calcium