GABAARs [GABA (γ-aminobutyric acid) type-A receptors] are heteropentameric chloride-selective ligand-gated ion channels that mediate fast inhibition in the brain and are key therapeutic targets for benzodiazepines, barbiturates, neurosteroids and general anaesthetics. In the brain, most of the benzodiazepine-sensitive synaptic receptor subtypes are assembled from α1-3, β1-3 and γ2 subunits. Although it is evident that the pharmacological manipulation of GABAAR function can have profound effects on behaviour, the endogenous mechanisms that neurons use to promote sustained changes in the efficacy of neuronal inhibition remain to be documented. It is increasingly clear that GABAARs undergo significant rates of constitutive endocytosis and regulate recycling processes that can determine the efficacy of synaptic inhibition. Their endocytosis is regulated via the direct binding of specific endocytosis motifs within the intracellular domains of receptor β1-3and γ2 subunits to the clathrin adaptor protein AP2 (adaptor protein 2). These binding motifs contain major sites of both serine and tyrosine phosphorylation within GABAARs. Their phosphorylation can have dramatic effects on binding to AP2. In the present review, we evaluate the role that these phospho-dependent interactions play in regulating the construction of inhibitory synapses, efficacy of neuronal inhibition and neuronal structure.

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