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The Dynamic Modulation of Gabaa Receptor Trafficking and Its Role in Regulating the Plasticity of Inhibitory Synapses

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The Dynamic Modulation of Gabaa Receptor Trafficking and Its Role in Regulating the Plasticity of Inhibitory Synapses Physiol Rev 91: 1009–1022, 2011 doi:10.1152/physrev.00015.2010 THE DYNAMIC MODULATION OF GABAA RECEPTOR TRAFFICKING AND ITS ROLE IN REGULATING THE PLASTICITY OF INHIBITORY SYNAPSES Mansi Vithlani, Miho Terunuma, and Stephen J. Moss Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts; and Department of Neuroscience, Physiology, and Pharmacology, University College London, London, United Kingdom Vithlani M, Terunuma M, Moss SJ. The Dynamic Modulation of GABAA Receptor Trafficking and Its Role in Regulating the Plasticity of Inhibitory Synapses. Physiol Rev 91: 1009–1022, 2011; doi:10.1152/physrev.00015.2010.—Inhibition in the adult mammalian central nervous system (CNS) is mediated by ␥-aminobutyric acid (GABA). The fast inhibitory actions of GABA are mediated by GABA type A receptors (GABAARs); Lthey 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. GABAARs 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 GABAAR subtypes at inhibitory synapses. Here we evaluate how neurons control the number of GABAARs 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. I. INTRODUCTION 1009 slow and prolonged inhibitory responses (10). GABAARs II. GABAA RECEPTOR STRUCTURE 1010 are clinically relevant drug targets for anticonvulsant, an- III. SUBUNIT COMPOSITION OF SYNAPTIC... 1011 xiolytic, and sedative-hypnotic agents including benzodi- IV. FUNCTIONAL SIGNIFICANCE OF GABAA... 1011 azepines, barbiturates, neurosteroids, certain classes of V. MEMBRANE TRAFFICKING OF GABAA... 1012 general anesthetics, and alcohol. These allosteric com- VI. EXOCYTOSIS OF GABAA RECEPTORS... 1012 pounds bind to discrete sites distinct from the agonist VII. ENDOCYTOSIS OF GABAA RECEPTORS... 1014 binding site to either positively or negatively modulate VIII. POSTENDOCYTIC GABAA... 1015 receptor function (69). IX. POSTSYNAPTIC TARGETING AND ... 1015 X. MODULATION OF GABAA RECEPTOR... 1017 The classic GABAAR-mediated hyperpolarization of the XI. CONCLUDING REMARKS 1019 membrane potential is attributed to the direct activation of an integral ion channel and the resultant influx of chloride I. INTRODUCTION along its electrochemical gradient. The concentration-re- sponse curve exhibits positive cooperativity consistent with Inhibition in the adult mammalian central nervous system the presence of at least two GABA binding sites on the (CNS) is mediated by ␥-aminobutyric acid (GABA). It is receptor complex (5). Following brief exposure to high estimated that at least one-third of all CNS neurons utilize (millimolar) concentrations of GABA (released from pre- GABA as their primary neurotransmitter. Most of these synaptic vesicles), activation of GABAARs located at synap- GABAergic neurons are interneurons and therefore are tic sites transiently moves the membrane potential away uniquely able to alter the excitability of local circuits within from the spike threshold required for action potential gen- a given brain region. GABA exerts its powerful inhibitory eration underlying what is known as “phasic” inhibition. In influence by acting on two distinct classes of receptors based contrast, low (submicromolar) concentrations of ambient on their electrophysiological and pharmacological proper- GABA in the extracellular space can persistently activate ties. Ionotropic GABA type A receptors (GABAARs) are spatially and temporally less-restricted extrasynaptic recep- fast-acting ligand-gated chloride channels (69), while tors to generate a persistent or “tonic” inhibitory state (29). metabotropic GABAB receptors are coupled indirectly via G Given the critical role of GABAARs in controlling neuronal proteins to either calcium or potassium channels to produce excitability and animal behavior, it is of fundamental im- 1009 GABA TYPE A RECEPTOR TRAFFICKING portance to understand the mechanisms used by neurons to nel (FIGURE 1), which in the case of the GABAAR is perme- regulate their function. able to chloride and, to a lesser extent, bicarbonate anions (81). Each subunit is predicted to share a common mem- Emerging evidence indicates that activity-dependent changes brane topology encompassing a large extracellular NH2- in the number of postsynaptic GABAARs represent one of terminal ligand-binding domain and four transmembrane the most powerful mechanisms underlying the functional (TM) 1–4 domains. A major cytoplasmic loop lies between plasticity of GABAergic synapses. Moreover, deficits in the TM3 and TM4 and is the most divergent part of the se- functional expression of GABA Rs have been implicated in A quence among the GABAAR subfamily. This intracellular the pathogenesis of a wide range of neurological and psy- domain (ICD) is the target for a number of posttranslational chiatric diseases including epilepsy, anxiety, depression, modifications that can directly affect channel function schizophrenia, and substance abuse. A significant amount and/or mediate the interaction with cytosolic proteins im- of research has thus focused on detailing the cellular and portant for regulating receptor localization and/or mem- molecular mechanisms that regulate the stability of brane trafficking. GABAARs on the cell surface and their accumulation at the inhibitory postsynapse. Comparative modeling of the GABAAR based on the 4-Å resolution model of the Torpedo nACh receptor for the first II. GABAA RECEPTOR STRUCTURE time provided an insight into the three-dimensional organi- zation of this ligand-gated ion channel (27). The extracel- GABA Rs belong to the superfamily of Cys-loop ligand- lular domain of each receptor subunit comprises a variable A ␤ gated ion channels that comprises nicotinic acetylcholine NH2-terminal domain and two -folded sheets that form a receptors (nAChRs), strychnine-sensitive glycine receptors, twisted sandwich connected by a signature disulfide bridge. ϩ Ϫ and 5-hydroxytryptamine type-3 receptors (5-HT3Rs). Each subunit has a principal ( ) and a complementary ( ) Members of this family are heteropentameric glycoproteins side. The GABA binding sites are located in solvent-acces- composed of homologous subunits that specifically recog- sible pockets at the two ␤ϩ␣Ϫ subunit interfaces and that nize one another and assemble around an intrinsic ion chan- of benzodiazepines at the ␣ϩ␥Ϫ interface (26). The TM FIGURE 1 GABAA receptor (GABAAR) structure. A: transmembrane topology of the GABAAR. Each receptor subunit is composed of a large extracellular ligand-binding NH2-terminal region that is also the site of action of various drugs followed by four hydrophobic transmembrane TM1–4 ␣-helices and a short, barely extruding COOH 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 posttranslational modifications. B: transverse view of the assembly of GABAAR 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. 1010 Physiol Rev • VOL 91 • JULY 2011 • www.prv.org VITHLANI, TERUNUMA, AND MOSS domain of the receptor is made up of four loosely packed GABAAR subunits. Instead they homo- and hetero-oli- helical bundles resulting in a considerable amount of sol- gomerize with other ␳ subunits to form a family of pharma- vent-accessible space within subunits and at the subunit cologically distinct GABA-gated chloride channels that interfaces. It has been proposed that the intersubunit pock- have been termed GABAC receptors (15). ets form a continuous groove with their extracellular coun- terparts, suggesting that they may not only play a role in the In addition to molecular determination of GABAAR assem- conformational mobility of the receptor but also provide bly, subunit composition is further restricted by the spatial putative drug-binding sites. and temporal pattern of subunit expression. In situ hybrid- ization and immunohistochemical studies have demon- The subunit interfaces contain a number of amino acid strated that each one of the subunits has a distinct regional residues that have been shown to be of key importance in and cellular distribution within the brain. Moreover, differ- the binding and/or efficacy of a number of modulatory ent subunits and/or subunit combinations further dictate drugs. For example, S270 in TM2 and A291 in TM3 in the the subcellular localization of these ligand-gated chloride ␣1 subunit are of importance for the actions of volatile channels and determine their biophysical and pharmaco- anesthetics (57). Similarly, an aspartic acid residue (R265) logical properties. Detailed knowledge of the molecular in the ␤2 and ␤3 subunit isoforms is believed to account for composition and the exact anatomical expression of differ- the subtype-selectivity of etomidate (8). Photoaffinity label- ent GABAAR subtypes are therefore crucial in understand- ing has also revealed that Met-236
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