Gamma-Aminobutyric Acid (GABA) Inhibits α-Melanocyte-Stimulating Hormone-Induced Melanogenesis through GABAA and GABAB Receptors

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 alpha-melanocyte-stimulating hormone (alpha-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, alpha-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 alpha-MSH stimulation, GABA-related antimelanogenic effects were mediated through the GABA(A) and GABA(B) receptors, with subsequent inhibition of Ca2+ accumulation. In B16F10 melanoma cells and zebrafish larvae, pretreatment with bicuculline, a GABA(A) receptor antagonist, and CGP 46381, a GABA(B) receptor antagonist, reversed the antimelanogenic effect of GABA following alpha-MSH treatment by upregulating Ca2+ accumulation. In conclusion, our results indicate that GABA inhibits alpha-MSH-induced melanogenesis. Hence, in addition to the health benefits of GABA in the central nervous system, it could ameliorate hyperpigmentation disorders.

Automated summary

The study demonstrates that GABA can significantly inhibit melanin synthesis by suppressing MITF and tyrosinase expression, reducing cAMP and CREB levels. GABA inhibits Ca2+ accumulation through GABA(A) and GABA(B) receptors, thereby reducing melanin production.