14-3-3ζ Mediates GABA_AR Activation by Interacting with BIG1

Most fast synaptic inhibitions in the mammalian brain are mediated by GABA_A receptors (GABA_ARs). An appropriate level of GABA_AR expression at the cell surface is essential for neurodevelopment and the efficacy of GABAergic synaptic transmission. We previously reported that brefeldin A-inhibited GDP/GTP exchange factor 1 (BIG1), a binding partner of GABA_ARs, plays an important role in trafficking GABA_ARs to the cell surface. However, its regulatory mechanisms remain unknown. In the present study, we identified a new cellular protein, 14-3-3ζ, which can interact with the β subunit of GABA_ARs and BIG1 both in vitro and in vivo and colocalizes in the soma, dendrites, and axons of hippocampal neurons. Overexpression of 14-3-3ζ-WT increased the surface expression of BIG1 in dendrites and axons, as well as the binding of BIG1 with GABA_AR. Depleted 14-3-3ζ with efficacious siRNA attenuated the interaction between BIG1 and GABA_ARs and resulted in significant decreases in the surface expression levels of BIG1 and GABA_AR. GABA_AR agonist treatment increased the expression levels of BIG1 and 14-3-3ζ on the surface, indicating that 14-3-3ζ is involved in regulating BIG1-mediated GABA_AR surface expression. Depletion of BIG1 or 14-3-3ζ significantly decreased GABA_AR expression at the cell surface and suppressed the GABA-gated influx of chloride ions. These data indicate that the combination of 14-3-3ζ and BIG1 is required for GABA_AR membrane expression. Our results provide a potential promising therapeutic target for neurological disorders involving GABAergic synaptic transmission.