Subunit composition, distribution and function of GABA(A) receptor subtypes.
TL;DR: Together, these results should cause a revival of GABA(A) receptor research and strongly stimulate the development of drugs with a higher selectivity for alpha2-, alpha3-, or alpha5-subunit-containing receptor subtypes.
Abstract: GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain and are the site of action of many clinically important drugs. These receptors are composed of five subunits that can belong to eight different subunit classes. Depending on their subunit composition, these receptors exhibit distinct pharmacological and electrophysiological properties. Recent studies on recombinant and native GABA(A) receptors suggest the existence of far more receptor subtypes than previously assumed. Thus, receptors composed of one, two, three, four, or five different subunits might exist in the brain. Studies on the regional, cellular and subcellular distribution of GABA(A) receptor subunits, and on the co-localization of these subunits at the light and electron microscopic level for the first time provide information on the distribution of GABA(A) receptor subtypes in the brain. These studies will have to be complemented by electrophysiological and pharmacological studies on the respective recombinant and native receptors to finally identify the receptor subtypes present in the brain. The distinct cellular and subcellular location of individual receptor subtypes suggests that they exhibit specific functions in the brain that can be selectively modulated by subtype specific drugs. This conclusion is supported by the recent demonstration that different GABA(A) receptor subtypes mediate different effects of benzodiazepines. Together, these results should cause a revival of GABA(A) receptor research and strongly stimulate the development of drugs with a higher selectivity for alpha2-, alpha3-, or alpha5-subunit-containing receptor subtypes. Such drugs might exhibit quite selective clinical effects.
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TL;DR: This review considers the distinct roles of synaptic and extrasynaptic GABA receptor subtypes in the control of neuronal excitability in the adult mammalian brain.
Abstract: The proper functioning of the adult mammalian brain relies on the orchestrated regulation of neural activity by a diverse population of GABA (gamma-aminobutyric acid)-releasing neurons. Until recently, our appreciation of GABA-mediated inhibition focused predominantly on the GABA(A) (GABA type A) receptors located at synaptic contacts, which are activated in a transient or 'phasic' manner by GABA that is released from synaptic vesicles. However, there is growing evidence that low concentrations of ambient GABA can persistently activate certain subtypes of GABA(A) receptor, which are often remote from synapses, to generate a 'tonic' conductance. In this review, we consider the distinct roles of synaptic and extrasynaptic GABA receptor subtypes in the control of neuronal excitability.
1,994 citations
TL;DR: GABAA (γ-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs.
Abstract: GABA(A) (gamma-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABA(A) receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABA(A) receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.
1,042 citations
TL;DR: This review attempts to summarize experimental evidence on the existence of defined native GABAA receptor subtypes and to produce a list of receptors that actually seem to exist according to current knowledge, and proposes several criteria, which can be applied to all the members of the LGIC superfamily, for including a receptor subtype on a lists of native hetero-oligomeric subtypes.
Abstract: In this review we attempt to summarize experimental evidence on the existence of defined native GABA(A) receptor subtypes and to produce a list of receptors that actually seem to exist according to current knowledge. This will serve to update the most recent classification of GABA(A) receptors (Pharmacol Rev 50:291-313, 1998) approved by the Nomenclature Committee of the International Union of Pharmacology. GABA(A) receptors are chloride channels that mediate the major form of fast inhibitory neurotransmission in the central nervous system. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share structural and functional homology with other members of that family. GABA(A) receptors are assembled from a family of 19 homologous subunit gene products and form numerous, mostly hetero-oligomeric, pentamers. Such receptor subtypes with properties that depend on subunit composition vary in topography and ontogeny, in cellular and subcellular localization, in their role in brain circuits and behaviors, in their mechanisms of regulation, and in their pharmacology. We propose several criteria, which can be applied to all the members of the LGIC superfamily, for including a receptor subtype on a list of native hetero-oligomeric subtypes. With these criteria, we develop a working GABA(A) receptor list, which currently includes 26 members, but will undoubtedly be modified and grow as information expands. The list is divided into three categories of native receptor subtypes: "identified," "existence with high probability," and "tentative."
989 citations
Cites background from "Subunit composition, distribution a..."
...Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single , two copies of a single , and one copy of another subunit, such as , , or (Sieghart and Sperk, 2002; Olsen and Sawyer, 2004)....
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...Other subunits are also colocalized with and have been shown to coprecipitate with all and the 2 subunits (Sieghart and Sperk, 2002)....
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...Recombinant 1 2 2 receptors have been shown to have a 2 -2 -1 2 stoichiometry [denoted ( 1)2( 2)2 2], and this stoichiometry is supported by coimmunoprecipitation results from rat or mouse brain (Sieghart and Sperk, 2002)....
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...…demonstrated by recombinant GABAA-Rs containing different subunits can also be found in the brain (Itier et al., 1996; Whiting et al., 2000; Sieghart and Sperk, 2002) and individual cells can be shown to exhibit more than one GABAA-R with varying affinity for zolpidem, depending on subunit…...
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...The 2 and 3 subunits are moderately abundant and 5 is relatively rare except in the hippocampus, as indicated by regional distribution and immunoprecipitation studies (Pirker et al., 2000; Sieghart and Sperk, 2002)....
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TL;DR: This mini-review attempts to update experimental evidence on the existence of GABA(A) receptor pharmacological subtypes and to produce a list of those native receptors that exist and proposes several criteria for including a receptor hetero-oligomeric subtype candidate on a lists of native subtypes, and a working GABA( A) receptor list.
865 citations
TL;DR: This Review discusses recent progress in the 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.
Abstract: γ-Aminobutyric acid type A (GABAA) receptors mediate the majority of fast synaptic inhibition in the mammalian brain, controlling activity both at the network and cellular level. The diverse functions of GABA in the central nervous system are matched not just by the heterogeneity of GABAA receptors, but also the complex trafficking mechanisms and protein-protein interactions that generate and maintain appropriate receptor cell surface localization. In this review, we discuss recent progress in our understanding of the dynamic regulation of GABAA receptor 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 GABAA receptor trafficking occur.
643 citations
Cites background from "Subunit composition, distribution a..."
...The fast inhibitory actions of GABA are mediated by the activation of GABA A receptors (GABA A Rs) in the brai...
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