Abstract
Gamma-aminobutyric acid (GABA) is considered the primary inhibitory neurotransmitter in the human cortex. However, whether GABA regulates melanogenesis has not been comprehensively elucidated. In this study, we reveal that GABA (20 mM) significantly inhibited α-melanocyte-stimulating hormone (α-MSH)-induced extracellular (from 354.9% ± 28.4% to 126.5% ± 16.0%) and intracellular melanin contents (from 236.7% ± 11.1% to 102.7% ± 23.1%) in B16F10 melanoma cells, without inducing cytotoxicity. In addition, α-MSH-induced hyperpigmentation in zebrafish larvae was inhibited from 246.3% ± 5.4% to 116.3% ± 3.1% at 40 mM GABA, displaying no apparent cardiotoxicity. We also clarify that the GABA-mediated antimelanogenic properties were related to the direct inhibition of microphthalmia-associated transcription factor (MITF) and tyrosinase expression by inhibiting cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB). Furthermore, under α-MSH stimulation, GABA-related antimelanogenic effects were mediated through the GABAA and GABAB receptors, with subsequent inhibition of Ca2+ accumulation. In B16F10 melanoma cells and zebrafish larvae, pretreatment with bicuculline, a GABAA receptor antagonist, and CGP 46381, a GABAB receptor antagonist, reversed the antimelanogenic effect of GABA following α-MSH treatment by upregulating Ca2+ accumulation. In conclusion, our results indicate that GABA inhibits α-MSH-induced melanogenesis. Hence, in addition to the health benefits of GABA in the central nervous system, it could ameliorate hyperpigmentation disorders.
Highlights
Melanin is a primary determinant of skin color that protects the skin from adverse external stimuli such as ultraviolet (UV) radiation [1]
To evaluate the cytotoxic effect of Gamma-aminobutyric acid (GABA) (Figure 1A) in B16F10 melanoma cells, the cells were treated with the indicated concentrations of GABA (0–100 mM) for 96 h, and cell viability was examined
These findings indicate that GABA inhibits α-melanocytestimulating hormone (α-MSH)-induced melanogenesis by inhibiting the cyclic adenosine monophosphate (cAMP)–cAMP response element-binding protein (CREB) axis and Ca2+ signaling pathways
Summary
Melanin is a primary determinant of skin color that protects the skin from adverse external stimuli such as ultraviolet (UV) radiation [1]. In response to UV radiation, αmelanocyte-stimulating hormone (α-MSH) is produced from the skin and pituitary gland, which mediates the onset of melanin production in melanocytes [2]. ΑMSH binds to the melanocortin 1 receptor (MC1R), stimulating the downstream signaling pathways through adenylyl cyclase (AC). AC catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), and, subsequently, the protein kinase A (PKA)–cAMP response element-binding protein (CREB) axis, which is mainly considered to promote melanogenesis through the transactivation of microphthalmia-associated transcription factor (MITF) [3]. The binding of α-MSH to MC1R is responsible for initiating store-operated Ca2+ entry pathways via Ca2+ release from the endoplasmic reticulum (ER) lumen into the cytosol [4]. Excessive melanin production can induce several diseases, including melasma, post-inflammatory hyperpigmentation, and cutaneous amyloidosis [7]
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