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

Myoung Eun Choi,Hanju Yoo,Sung Eun Chang,Woo Jin Lee,Ik Joon Moon,Ha-Ri Lee,Youngsup Song

doi:10.3390/ijms21228796

Abstract

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.

Highlights

A wide range of pigmentary skin disorders have a significant psychological and social impact on patients
The binding of catecholamines to the G protein-coupled receptors (GPCRs) triggers the activation of intracellular adenylate cyclase, which synthesizes 3,5 -cyclic adenosine monophosphate from ATP [10]
The cytotoxicity of carvedilol against normal human melanocytes (NHMs) and Mel-ab cells was assessed by a WST cell proliferation assay

Summary

Introduction

A wide range of pigmentary skin disorders have a significant psychological and social impact on patients. Various treatment modalities, including systemic and topical agents as well as laser therapy, have been developed [1,2,3]. Catecholamines, which include dopamine, epinephrine, and norepinephrine, are signaling molecules that act as neurotransmitters and endocrine hormones. The biosynthesis and degradation of catecholamines occur in human keratinocytes, but catecholamine synthesis in melanocytes is somewhat different [7,8,9]. The binding of catecholamines to the GPCRs triggers the activation of intracellular adenylate cyclase, which synthesizes 3 ,5 -cyclic adenosine monophosphate (cAMP) from ATP [10]. GPCRs are activated by amines and peptides, including glucagon, parathyroid hormone, secretin, and calcitonin [10]

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