14-3-3ζ Mediates GABAR Activation by Interacting with BIG1.

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