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

作者：Li, Cuixian; Huang, Shen; Peng, Jin; Hong, Tianguo; Zhou, Chun^*; Tang, Jie^*

来源：Molecular Neurobiology, 2023, 60(3): 1721-1732.

DOI：10.1007/s12035-022-03172-z

• GABA(A) receptors
• BIG1
• 14-3-3 zeta
• Trafficking

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, 14-3-3 zeta, which can interact with the beta 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 14-3-3 zeta-WT increased the surface expression of BIG1 in dendrites and axons, as well as the binding of BIG1 with GABA(A)R. Depleted 14-3-3 zeta 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 14-3-3 zeta on the surface, indicating that 14-3-3 zeta is involved in regulating BIG1-mediated GABA(A)R surface expression. Depletion of BIG1 or 14-3-3 zeta 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 14-3-3 zeta 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.

• 单位
  中山大学; 南方医科大学