Figure 1.

GABA_A receptor (GABA_AR) trafficking under physiologic condition. (1) GABA_AR are assembled in the ER. (2) In the ER, unassembled receptor subunits are subjected to poly-ubiquitination and targeted for proteasomal degradation. (3) GABA_AR transport to the Golgi is a process negatively regulated by Plic-1. Inside the Golgi, GABA_AR bind to GABA_AR associated protein (GABARAP)/N-ethylmaleimide-sensitive factor (NSF) complex that facilitates their transport to the plasma membrane. The delivery of GABA_AR to the plasma membrane is also regulated by GODZ, Big2, glutamate receptor-interacting protein (GRIP) and PRIP. (4) At the plasma membrane, GABA_AR quickly exchange between synaptic and extrasynaptic locations, and the accumulation of the receptor at the inhibitory synapses is regulated by its scaffold protein gephyrin. (5) The phosphorylation of β3 or γ2 GABA_AR subunits on their intracellular loop negatively regulates GABA_AR internalization. (6) The process of GABA_AR endocytosis is AP2/clathrin/dynamin-mediated. (7) Most internalized GABA_AR are rapidly recycled back to the plasma membrane by a mechanism dependent of the interaction with huntingtin-associated protein 1 (HAP1). (8) The non-recycled GABA_AR are targeted for lysosomal degradation.