The dynamic modulation of GABA(A) receptor trafficking and its role in regulating the plasticity of inhibitory synapses

Abstract

Inhibition in the adult mammalian central nervous system (CNS) is mediated by γ-aminobutyric acid (GABA). The fast inhibitory actions of GABA are mediated by GABA type A receptors (GABA(A)Rs); they mediate both phasic and tonic inhibition in the brain and are the principle sites of action for anticonvulsant, anxiolytic, and sedative-hypnotic agents that include benzodiazepines, barbiturates, neurosteroids, and some general anesthetics. GABA(A)Rs are heteropentameric ligand-gated ion channels that are found concentrated at inhibitory postsynaptic sites where they mediate phasic inhibition and at extrasynaptic sites where they mediate tonic inhibition. The efficacy of inhibition and thus neuronal excitability is critically dependent on the accumulation of specific GABA(A)R subtypes at inhibitory synapses. Here we evaluate how neurons control the number of GABA(A)Rs on the neuronal plasma membrane together with their selective stabilization at synaptic sites. We then go on to examine the impact that these processes have on the strength of synaptic inhibition and behavior.

Figure 1. GABA_AR structure

(A) Transmembrane topology of the GABA_AR. Each receptor subunit is composed of a large extracellular ligand-binding N-terminal region that is also the site of action of various drugs followed by four hydrophobic transmembrane (TM)1–4 α-helices and a short, barely extruding C-terminus. Each receptor subunit also contains a large intracellular domain (ICD) between TM3 and TM4 that mediates the majority of protein-protein interactions and is subject to a number of post-translational modifications. (B) Traverse view of the assembly of GABA_AR subunits to form an ion channel. TM2 faces the lumen of the channel ion pore and TM4 is anchored in the lipid membrane. TM1 and TM3 interact with the neighboring subunits.

Figure 2. Clathrin-mediated endocytosis

The receptors cluster in specialized sites at the plasma membrane known as clathrin-coated pits, which invaginate and pinch off to form clathrin-coated vesicles (CCVs), a process that is dependent on dynamin. The clathrin adaptor protein (AP)-2 is a central component in the formation of these vesicles, forging a link between membrane proteins and clathrin that forms the outer layer of the coat. The vesicles subsequently lose their coat and fuse together to form an early endosome. Internalized receptors are then either subject to rapid recycling or are targeted for lysosomal degradation, an endocytic sorting decision that is regulated by the Huntingtin-associated protein (HAP)-1.