GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition

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Abstract
GABA (γ-aminobutyric acid) type A receptors (GABAARs) are GABA-gated, Cl−-selective channels that are responsible for most fast synaptic inhibition in the mammalian brain. GABAARs at extrasynaptic sites also have crucial roles in mediating tonic inhibition in the brain. In addition, GABAARs are clinically relevant drug targets for many sedative–hypnotic, anxiolytic, anti-convulsant and general-anaesthetic agents. GABAARs are synthesized and assembled in the endoplasmic reticulum (ER) to form select pentameric receptor populations that each have distinct physiological and pharmacological properties, as well as differential subcellular targeting and expression throughout the brain. The ER-associated degradation of GABAAR subunits by the ubiquitin–proteasome system is one mechanism that neurons use to regulate the number of GABAARs that are exported from the ER. New research suggests that synaptic activity can bidirectionally regulate this degradation process. Numerous proteins have been identified that interact with GABAARs in the Golgi apparatus, to help them segregate and exit the Golgi in the appropriate transport vesicles. This helps the GABAARs traffic to the appropriate destination on the plasma membrane. Post-translational modifications, such as phosphorylation and palmitoylation, have been demonstrated to be of crucial importance in dynamically modulating these protein–protein interactions and in influencing GABAAR trafficking to the plasma membrane. Lateral diffusion of GABAARs in the plasma membrane allows continual exchange between synaptic and extrasynaptic receptor populations, with inhibitory scaffold molecules tethering or corralling moving receptors. The inhibitory scaffold is also a dynamic entity that displays local lateral movements and rapid intracellular transport to or from the synapse. These mechanisms contribute to the regulation of receptor cell-surface localization and synaptic strength. Clathrin-dependent endocytosis is the major internalization mechanism for neuronal GABAARs. It depends on interactions between the intracellular loops of GABAAR subunits and the clathrin-adaptor protein (AP2) complex. Phosphorylation of GABAAR subunits at distinct AP2 binding sites seems to regulate receptor stability at the cell surface and, consequently, the strength of synaptic inhibition. Once they have been endocytosed, GABAARs can be recycled to the plasma membrane or degraded in lysosomes, a complex process that is likely to be regulated at multiple points. Dysregulation of GABAAR expression and trafficking has been implicated in a number of neurological and neuropsychiatric disorders, including epilepsy, drug abuse disorders and schizophrenia.