GABAA receptors: properties and trafficking. Crit Rev Biochem Mol Biol

Department of Neuroscience, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104-6074, USA.
Critical Reviews in Biochemistry and Molecular Biology (Impact Factor: 7.71). 01/2007; 42(1):3-14. DOI: 10.1080/10409230601146219
Source: PubMed

ABSTRACT Fast synaptic inhibition in the brain and spinal cord is mediated largely by ionotropic gamma-aminobutyric acid (GABA) receptors. GABAA receptors play a key role in controlling neuronal activity; thus modulating their function will have important consequences for neuronal excitation. GABAA receptors are important therapeutic targets for a range of sedative, anxiolytic, and hypnotic agents and are involved in a number of CNS diseases, including sleep disturbances, anxiety, premenstrual syndrome, alcoholism, muscle spasms, Alzheimer's disease, chronic pain, schizophrenia, bipolar affective disorders, and epilepsy. This review focuses on the functional and pharmacological properties of GABAA receptors and trafficking as an essential mechanism underlying the dynamic regulation of synaptic strength.

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    • "The final destination of GABA A R into synaptic or extrasynaptic sites is intrinsically determined by the subunits forming the channels and extrinsically by protein– protein interactions with scaffolding proteins (Luscher and Keller, 2004; Chen and Olsen, 2007; Jacob et al., 2008; Leidenheimer, 2008). Gephyrin is the main structural scaffold that links proteins located at the subsynaptic compartment with the cytoskeleton and it is required for the organization and clustering of GABA A R at inhibitory synapses (Michels and Moss, 2007; Fritschy et al., 2008). "
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    ABSTRACT: The term epileptogenesis refers to a dynamic alteration in neuronal excitability that promotes the appearance of spontaneous seizures. Temporal lobe epilepsy, the most common type of acquired epilepsy, often develops after an insult to the brain such as trauma, febrile seizures, encephalitis, or status epilepticus. During the pre-epileptic state (also referred as latent or silent period) there is a plethora of molecular, biochemical, and structural changes that lead to the generation of recurrent spontaneous seizures (or epilepsy). The specific contribution of these alterations to epilepsy development is unclear, but a loss of inhibition has been associated with the increased excitability detected in the latent period. A rapid increase in neuronal hyperexcitability could be due, at least in part, to a decline in the number of physiologically active GABAA receptors (GABAAR). Altered expression of scaffolding proteins involved in the trafficking and anchoring of GABAAR could directly impact the stability of GABAergic synapses and promote a deficiency in inhibitory neurotransmission. Uncovering the molecular mechanisms operating during epileptogenesis and its possible impact on the regulation of GABAAR and scaffolding proteins may offer new targets to prevent the development of epilepsy.
    Frontiers in Cellular Neuroscience 07/2013; 7:113. DOI:10.3389/fncel.2013.00113 · 4.29 Impact Factor
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    • "GABAA and glycine receptors belong to the cys-loop superfamily of ligand-gated ion channels [5], [6]. As they are both permeable to chloride ions, activation of these receptors causes inhibition of neuronal excitability in the central nervous system. "
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    ABSTRACT: Background: The ventral horn is a major substrate in mediating the immobilizing properties of the volatile anesthetic sevoflurane in the spinal cord. In this neuronal network, action potential firing is controlled by GABA(A) and glycine receptors. Both types of ion channels are sensitive to volatile anesthetics, but their role in mediating anesthetic-induced inhibition of spinal locomotor networks is not fully understood. Methodology/Principal Findings: To compare the effects of sevoflurane on GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) whole-cell voltage-clamp recordings from ventral horn interneurons were carried out in organotypic spinal cultures. At concentrations close to MAC (minimum alveolar concentration), decay times of both types of IPSCs were significantly prolonged. However, at 1.5 MAC equivalents, GABAergic IPSCs were decreased in amplitude and reduced in frequency. These effects counteracted the prolongation of the decay time, thereby decreasing the timeaveraged GABAergic inhibition. In contrast, amplitudes and frequency of glycinergic IPSCs were not significantly altered by sevoflurane. Furthermore, selective GABA(A) and glycine receptor antagonists were tested for their potency to reverse sevoflurane-induced inhibition of spontaneous action potential firing in the ventral horn. These experiments confirmed a weak impact of GABA(A) receptors and a prominent role of glycine receptors at a high sevoflurane concentration. Conclusions: At high concentrations, sevoflurane mediates neuronal inhibition in the spinal ventral horn primarily via glycine receptors, and less via GABA(A) receptors. Our results support the hypothesis that the impact of GABA(A) receptors in mediating the immobilizing properties of volatile anesthetics is less essential in comparison to glycine receptors.
    PLoS ONE 04/2013; 8(4):e60286. DOI:10.1371/journal.pone.0060286 · 3.23 Impact Factor
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    • "Genetic association of recovery from eating disorders CS Bloss et al mediated either by GABA-A receptors, which are ionotropic GABA-gated chloride channel receptors, or by the metabotropic GABA-B receptors. GABA-A receptors are heteromeric pentamers composed of five subunits that can belong to different subfamilies (Michels and Moss, 2007). "
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    ABSTRACT: Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, 'ill') or absence (n=115 no symptoms in the past year, ie, 'recovered') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10(-6), false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10(-6), FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (γ-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2011; 36(11):2222-32. DOI:10.1038/npp.2011.108 · 7.05 Impact Factor
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