title: Enhancing pigmentation via activation of A3 adenosine receptors in B16 melanoma cells and in human skin explants.
abstract: A3 adenosine receptor, A3AR, belongs to the Gi proteins coupled receptors. Activation of A3AR by its agonist, IB-MECA, decreases cAMP and was expected to reduce melanin level. Unexpectedly, B16 melanoma cells exposed to IB-MECA increased melanin levels in a dose-dependent manner. Human skin explants exposed to IB-MECA showed an increase in DOPA positive cells and in melanin deposition in keratinocytes. The agonist induced AKT phosphorylation, leading to a rapid translocation of the transcription factor MiTF towards the nucleus. DOPA oxidase activity and melanin levels induced by IB-MECA were further enhanced by PD98509, an inhibitor ERK signalling pathway. Our study shows that IB-MECA decreases cAMP while inducing melanogenesis. The proposed mechanism involves activation of PI3K/AKT signalling pathway by β/γ subunits of the G protein coupled to A3AR. The increase in melanin level in human skin explants suggests that IB-MECA may be a potential candidate to the treatment of hypopigmentation of skin.
authors.forename: Lea
authors.initials: L
authors.lastname: Madi
authors.forename: Bianca
authors.initials: B
authors.lastname: Rosenberg-Haggen
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Rafi
authors.initials: R
authors.lastname: Korenstein
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008546:Melanoma, Experimental / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D014442:Monophenol Monooxygenase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010858:Pigmentation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D047428:Protein Kinase Inhibitors; D043684:Receptor, Adenosine A3; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D004295:Dihydroxyphenylalanine; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000241:Adenosine; D000077191:Wortmannin