As a Histone Deacetylase Inhibitor, γ‐Aminobutyric Acid Upregulates GluR2 Expression: An In Vitro and In Vivo Study

SCOPE: γ-Aminobutyric acid (GABA) possesses extensive physiological functions and can be directly obtained from foods. GABA-enriched functional foods have been developed and the commercial demands for GABA are increasing. GABA is widely recognized as a central nervous system inhibitory neurotransmitter and plays an important role in some diseases by binding to its receptors. However, some of the functions of GABA are not explained by neurotransmission or GABA receptor pathways. Therefore, this study investigates whether GABA has the potential to inhibit histone deacetylase (HDAC). METHODS AND RESULTS: It is found that GABA inhibits HDAC1/2/3 expression and upregulates histone acetylation levels (Ace-H3K9/Ace-H4K12) in SH-SY5Y cells (which express GABA receptors), 3T3-L1 cells (which do not express GABA receptors), and the cerebral cortex in mice. Glutamate receptor 2 (GluR2) is a subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor and is implicated in the pathogenesis of some neurological diseases. It is also found that GABA increases GluR2 expression by inhibiting HDAC1/2 but not HDAC3. CONCLUSION: A novel role for GABA is demonstrated in which it acts as an HDAC inhibitor. The present study expands the horizons for exploring the non-neurotransmitter functions of GABA.