Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA_A Receptor Modulators?

Figure 2

GABA_Areceptor trafficking and associated proteins. GABA_A receptors are assembled from individual subunits in the endoplasmatic reticulum (ER) where the chaperones BiP and Calnexin assist in quality control. Unassembled GABA_A receptor subunits that are to be targeted for ER-associated degradation are ubiquitinated and degraded in the proteasome. The ubiquitin-like protein PLIC can interact with GABA_A receptors thereby inhibiting their targeting for proteasomal degradation. Assembled pentameric GABA_A receptors exit the ER and bind the guanidine exchange factor brefeldin-A-inhibited GDP/GTP exchange factor 2 (BIG2) in the Golgi. Here they also interact with the palmitoylase transferase GODZ and Gamma-aminobutyric acid receptor-associated protein (GABARAP). GABARAP interacts with the NEM sensitive fusion (NSF) protein, as does the GABA_A receptor β subunit, and this association may facilitate transport of the receptor complexes to the cell surface. GABA_A receptors are inserted at extrasynaptic sites and can diffuse along the plasma membrane in and out of synaptic domains. At synapses they are stabilized by an interaction with the scaffolding protein Gephyrin. The interaction of the GABA_A receptor intracellular loops with the μ2 subunit of the adaptin complex AP2 is important for GABA_A receptor internalization. GABA_A receptors are delivered by a clathrin-mediated pathway to early endosomes where they can be targeted for degradation in the lysosome or for recycling upon binding of Huntington-associated protein (HAP1). Reprinted by permission from Elsevier, reprinted from [101].