14-3-3ζ Mediates GABA A R Activation by Interacting with BIG1.

Most fast synaptic inhibitions in the mammalian brain are mediated by GABA A receptors (GABA A Rs). An appropriate level of GABA A R 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 A Rs, plays an important role in trafficking GABA A Rs 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 A Rs 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 A R. Depleted 14-3-3ζ with efficacious siRNA attenuated the interaction between BIG1 and GABA A Rs and resulted in significant decreases in the surface expression levels of BIG1 and GABA A R. GABA A R 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 A R surface expression. Depletion of BIG1 or 14-3-3ζ significantly decreased GABA A R 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 A R membrane expression. Our results provide a potential promising therapeutic target for neurological disorders involving GABAergic synaptic transmission.