Regulation of GABA_A-receptor surface expression with special reference to the involvement of GABARAP (GABA_A receptor-associated protein) and PRIP (phospholipase C-related, but catalytically inactive protein)

GABA_A receptors are heteropentameric ligand-gated chloride channels composed of a variety of subunits, including α1 - 6, β1 - 3, γ1 - 3, δ, ε, θ, and π, and play a key role in controlling inhibitory neuronal activity. Modification of the efficacy of the synaptic strength is produced by changes in both the number of neuronal surface receptors and pentameric molecular assembly, leading to differences of sensitivity to neurotransmitters and neuromimetic drugs. Therefore, it is important to understand the molecular mechanisms regulating the so-called "life cycle of GABA_A receptors" including sequential pentameric assembly at the site synthesized, intracellular transport through the Golgi apparatus and the cytoplasm, insertion into the cell membrane, functional modulation at the cell surface, and finally internalization, followed by either recycling back to the surface membrane or lysosomal degradation. This review is focused on events related to the surface expression of the receptor containing the γ2 subunit and clathrin /AP2 complex-mediated phospho-regulated endocytosis of the receptor, with special reference to the function of novel GABA_A receptor modulators, GABARAP (GABA_A receptor-associated protein) and PRIP (phospholipase C-related, but catalytically inactive protein).