Key Points
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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.
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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.
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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.
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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.
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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.
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Dysregulation of GABAAR expression and trafficking has been implicated in a number of neurological and neuropsychiatric disorders, including epilepsy, drug abuse disorders and schizophrenia.
Abstract
GABA (γ-aminobutyric acid) type A receptors (GABAARs) mediate most fast synaptic inhibition in the mammalian brain, controlling activity at both the network and the cellular levels. The diverse functions of GABA in the CNS are matched not just by the heterogeneity of GABAARs, but also by the complex trafficking mechanisms and protein–protein interactions that generate and maintain an appropriate receptor cell-surface localization. In this Review, we discuss recent progress in our understanding of the dynamic regulation of GABAAR composition, trafficking to and from the neuronal surface, and lateral movement of receptors between synaptic and extrasynaptic locations. Finally, we highlight a number of neurological disorders, including epilepsy and schizophrenia, in which alterations in GABAAR trafficking occur.
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Acknowledgements
In memory of Professor Robert Eisenthal, the 'master enzymologist'. SJM is supported by NIH grants NS046478, NS048045, NS051195, NS056359 and P01NS054900 and by the MRC (UK) and the Wellcome Trust. The authors would like to thank R. Olsen for communication of unpublished results.
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Glossary
- Tonic inhibition
-
An inhibitory response that results from the activation of extra- or perisynaptic GABAA receptors by ambient concentrations of GABA.
- Benzodiazepines
-
Pharmacologically active molecules with sedative, anxiolytic, amnesic and anticonvulsant effects. They act by binding at the interface between the α(1, 2, 3 or 5) and γ subunits of GABAA receptors and potentiating the response elicited by GABA.
- Ubiquitin–proteasome system
-
(UPS). Ubiquitin is a 76-amino-acid protein that, among other functions, tags proteins for degradation. Tagged proteins are targeted to the proteasome, a large, multimeric barrel-like complex that degrades proteins.
- Palmitoylation
-
The covalent attachment of a palmitate (16-carbon saturated fatty acid) molecule to a cysteine residue through a thioester bond.
- RNA interference
-
(RNAi). A molecular method in which small interfering RNA sequences are introduced into cells or tissues to decrease the expression of target genes.
- Yeast two-hybrid screen
-
A system used to determine whether two proteins interact. It involves the expression of two proteins in yeast: the plasmids encoding these proteins are fused to the GAL4 DNA-binding and activation domains. If the proteins interact, the resulting complex drives the expression of a reporter gene, commonly β-galactosidase.
- Miniature inhibitory postsynaptic current
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(mIPSC). The postsynaptic current that results from the activation of synaptic receptors by neurotransmitters (GABA or glycine) that are usually released from a single vesicle.
- Clathrin
-
One of the main protein components of the coat that is formed during membrane endocytosis.
- Clathrin-adaptor protein 2 (AP2) complex
-
A heterotetrameric complex composed of subunits called adaptins that have an important role in clathrin-dependent membrane endocytosis.
- GABAergic plasticity
-
Changes in local activity that lead to longer-term increases or decreases in inhibitory synaptic strength.
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Jacob, T., Moss, S. & Jurd, R. GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci 9, 331–343 (2008). https://doi.org/10.1038/nrn2370
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DOI: https://doi.org/10.1038/nrn2370
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