CAMP-dependent activation of protein kinase A as a therapeutic target of skin hyperpigmentation by diphenylmethylene hydrazinecarbothioamide

Hyoeun Shin, Seung Deok Hong, Eunmiri Roh, Sang Hun Jung, Won Jea Cho, Sun Hong Park, Da Young Yoon, Seon Mi Ko, Bang Yeon Hwang, Jin Tae Hong, Tae Young Heo, Sang Bae Han, Youngsoo Kim

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25 Scopus citations


Background and Purpose cAMP as a second messenger stimulates expression of microphthalmia-associated transcription factor (MITF) or the tyrosinase gene in UVB-induced skin pigmentation. Diphenylmethylene hydrazinecarbothioamide (QNT 3-80) inhibits α-melanocyte-stimulating hormone (α-MSH)-induced melanin production in B16 murine melanoma cells but its molecular basis remains to be defined. Here, we investigated the mechanism underlying the amelioration of skin hyperpigmentation by QNT 3-80. Experimental Approach We used melanocyte cultures with raised levels of cAMP and UVB-irradiated dorsal skin of Guinea pigs for pigmentation assays. Immunoprecipitation, kemptide phosphorylation, fluorescence analysis and docking simulation were applied to elucidate a molecular mechanism of QNT 3-80. Key Results QNT 3-80 inhibited melanin production in melanocyte cultures with elevated levels of cAMP, including those from human foreskin. This compound also ameliorated hyperpigmentation in vivo in UVB-irradiated dorsal skin of Guinea pigs. As a mechanism, QNT 3-80 directly antagonized cAMP binding to the regulatory subunit of PKA, nullified the dissociation and activation of inactive PKA holoenzyme in melanocytes and fitted into the cAMP-binding site on the crystal structure of human PKA under the most energetically favourable simulation. QNT 3-80 consequently inhibited cAMP- or UVB-induced phosphorylation (activation) of cAMP-responsive element-binding protein in vitro and in vivo, thus down-regulating expression of genes for MITF or tyrosinase in the melanogenic process. Conclusions and Implications Our data suggested that QNT 3-80 could contribute significantly to the treatment of skin disorders with hyperpigmented patches with the cAMP-binding site of PKA as its molecular target.

Original languageEnglish (US)
Pages (from-to)3434-3445
Number of pages12
JournalBritish Journal of Pharmacology
Issue number13
StatePublished - Jul 1 2015

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© 2015 The British Pharmacological Society.


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