Carvedilol, an Adrenergic Blocker, Suppresses Melanin Synthesis by Inhibiting the cAMP/CREB Signaling Pathway in Human Melanocytes and Ex Vivo Human Skin Culture

• Published in: International journal of molecular sciences Vol. 21; no. 22; p. 8796
• Main Authors: Choi, Myoung Eun, Yoo, Hanju, Lee, Ha-Ri, Moon, Ik Joon, Lee, Woo Jin, Song, Youngsup, Chang, Sung Eun
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.11.2020; MDPI
• Subjects: Adenosine monophosphate; Adrenergic alpha-1 Receptor Antagonists - pharmacology; adrenergic blocker; Adrenergic receptors; Animals; Antioxidants; Biosynthesis; cAMP/CREB signaling; carvedilol; Carvedilol - pharmacology; Catecholamine; Catecholamines; Cell culture; Cell Line; Cell viability; Cyclic AMP - metabolism; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cytotoxicity; Forskolin; G protein-coupled receptors; Hormones; Humans; Intracellular levels; Kinases; Melanin; melanin synthesis; Melanins - biosynthesis; Melanocytes; Melanocytes - cytology; Melanocytes - drug effects; Melanocytes - metabolism; Mice; Microphthalmia-associated transcription factor; Phosphors; Pigmentation; Protein kinase A; Proteins; Receptor mechanisms; Receptors (physiology); Regulation; Signal transduction; Signal Transduction - drug effects; Skin; Skin - cytology; Skin - drug effects; Skin - metabolism; Skin Pigmentation - drug effects; Tyrosinase; melanin synthesis; cAMP/CREB signaling; carvedilol; adrenergic blocker
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21228796

Catecholamines function via G protein-coupled receptors, triggering an increase in intracellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) in various cells. Catecholamine biosynthesis and the β-adrenergic receptor exist in melanocytes; thus, catecholamines may play critical roles in skin pigmentation. However, their action and mechanisms mediating melanogenesis in human skin have not yet been investigated. Therefore, we examined the potential anti-melanogenetic effect of carvedilol, a nonselective β-blocker with weak α1-blocking activities. Carvedilol reduced melanin content and cellular tyrosinase activity without compromising cellular viability in normal human melanocytes as well as in mel-Ab immortalized mouse melanocytes. Carvedilol downregulated microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. Carvedilol treatment led to the downregulation of phosphor-cAMP response element-binding protein (CREB). Moreover, the increase in cAMP levels upon treatment with forskolin reversed the anti-melanogenic action of carvedilol. In addition, carvedilol remarkably reduced the melanin index in ultraviolet-irradiated human skin cultures. Taken together, our results indicate that carvedilol effectively suppresses melanogenesis in human melanocytes and ex vivo human skin by inhibiting cAMP/protein kinase A/CREB signaling. The anti-melanogenic effects of carvedilol have potential significance for skin whitening agents.