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

Abstract

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.

Advances in Nutritional Epigenetics—A Fresh Perspective for an Old Idea. Lessons Learned, Limitations, and Future Directions

“…GABA is an inhibitory neurotransmitter found abundantly in almost all organisms and therefore can be obtained directly from many foods. 247 It is found in over 20 peripheral tissues 248 , and in all regions of the central nervous system. 249 GABA is renowned for its high potency.…”

“… 251 Moreover; GABA was revealed to successfully inhibit class I, II and III histone deacetylases, upregulate H3K9 acetylation and H4K12 acetylation in SH-SY5Y cells; therefore, we cannot rule out epigenetic modulation that may rapidly influence gene expression beyond the BBB. 247 In addition, neurosteroids are highly lipophilic and therefore, readily cross the BBB. 252 Plasma and brain synthesised neurosteroids have demonstrated rapid effects on neuro-excitability via modulation of the GABA-a receptor.…”

MeBib Suppressed Methamphetamine Self-Administration Response via Inhibition of BDNF/ERK/CREB Signal Pathway in the Hippocampus

“…Furthermore, several studies have shown that HDAC inhibitors regulate glutamate receptor expression. ( Bhattacharya et al ., 2017 ; Xing et al ., 2019 ), however, the molecular mechanisms are poorly understood. We found for the first time MeBib, a HDAC6 inhibitor, suppressed the MA seeking response.…”

The molecular mechanism of γ-aminobutyric acid against AD: the role of CEBPα/circAPLP2/miR-671-5p in regulating CNTN1/2 expression

“…SH-SY5Y cells were inoculated in six-well cell culture plates and cultured into a sub-confluent state. According to our previous study, 21 the cells were pretreated with GABA at a final concentration of 10 nM for 3 h, and then exposed to a final concentration of 10 μM of Aβ. The culture medium was removed after continuous incubation for 24 h, and the cells were washed with phosphate-buffered saline and collected for qRT-PCR and western blotting assays.…”