The ion channel activator CyPPA inhibits melanogenesis via the GSK3β/β-catenin pathway

Abstract Research into materials that inhibit melanogenesis in skin has gained interest. Screening for such compounds in B16F10 cells revealed that cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), a positive modulator of small-conductance Ca 2+ -activated K + channels, is a strong inhibitor of melanogenesis. We investigated the anti-melanogenic activity of CyPPA and the molecular mechanism by which CyPPA reduced melanin production in normal human melanocytes (NHM). CyPPA treatment resulted in a significant concentration-dependent reduction in melanin content without significant cytotoxicity; treatment likewise resulted in a significant time-dependent reduction in tyrosinase (TYR) activity. Treatment with CyPPA also decreased transcription of melanogenesis-related genes, including the gene encoding microphthalmia-associated transcription factor (MITF). In addition, visual evaluation of the MelanoDerm™ human skin model revealed significantly lower melanin content in the CyPPA-treated condition than in the untreated control. CyPPA was determined to modulate glycogen synthase kinase-3β (GSK3β) activity, thereby leading to a decrease in β-catenin/MITF expression. Thus, CyPPA acts as a melanogenesis inhibitor by modulating the GSK3β/β-catenin/MITF pathway.