The role of GABAAR phosphorylation in the construction of inhibitory synapses and the efficacy of neuronal inhibition.
GABA(A)Rs [GABA (gamma-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 alpha(1-3), beta(1-3) and gamma(2) subunits. Although it is evident that the pharmacological manipulation of GABA(A)R 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 GABA(A)Rs 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 beta(1-3) and gamma(2) subunits to the clathrin adaptor protein AP2 (adaptor protein 2). These binding motifs contain major sites of both serine and tyrosine phosphorylation within GABA(A)Rs. 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.
Vithlani
Mansi
M
Department of Neuroscience, Tufts University, 136 Harrison Ave, Boston, MA 02111, USA.
Moss
Stephen J
SJ
D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D009433:Neural Inhibition / Q000502:physiology*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
D033962:Adaptor Protein Complex 2; D020033:Protein Isoforms; D021122:Protein Subunits; D011963:Receptors, GABA-A