ArticleMolecular pharmacology2010
An epilepsy-related region in the GABA(A) receptor mediates long-distance effects on GABA and benzodiazepine binding sites.
Article in Molecular pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 43 citations in OpenAlex.
- GABABiophysical journal · 2024Article
- Benzodiazepine Modulation of GABABiomolecules · 2022Review
- Why won't it stop? The dynamics of benzodiazepine resistance in status epilepticus.Nature reviews. Neurology · 2022Review
- Article
- A critical residue in the αeLife · 2021Article
- β11-12 linker isomerization governs acid-sensing ion channel desensitization and recovery.eLife · 2020Article
- SAHA (Vorinostat) Corrects Inhibitory Synaptic Deficits Caused by Missense Epilepsy Mutations to the GABAFrontiers in molecular neuroscience · 2018Article
- Desformylflustrabromine Modulates α4β2 Neuronal Nicotinic Acetylcholine Receptor High- and Low-Sensitivity Isoforms at Allosteric Clefts Containing the β2 Subunit.The Journal of pharmacology and experimental therapeutics · 2015Article
- Regulation of GABAARs by phosphorylation.Advances in pharmacology (San Diego, Calif.) · 2015Review
- A nonequilibrium binary elements-based kinetic model for benzodiazepine regulation of GABAA receptors.The Journal of general physiology · 2014Article
- Co-expression of γ2 subunits hinders processing of N-linked glycans attached to the N104 glycosylation sites of GABAA receptor β2 subunits.Neurochemical research · 2014Article
- Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner.Frontiers in cellular neuroscience · 2014Article
- Long distance effect on ligand-gated ion channels extracellular domain may affect interactions with the intracellular machinery.Communicative & integrative biology · 2014Article
- Agonist-dependent endocytosis of γ-aminobutyric acid type A (GABAA) receptors revealed by a γ2(R43Q) epilepsy mutation.The Journal of biological chemistry · 2013Article
- Article
- Neurochemical and behavioral features in genetic absence epilepsy and in acutely induced absence seizures.ISRN neurology · 2013Article
- Possible alterations in GABAA receptor signaling that underlie benzodiazepine-resistant seizures.Epilepsia · 2012Review
- Structural link between γ-aminobutyric acid type A (GABAA) receptor agonist binding site and inner β-sheet governs channel activation and allosteric drug modulation.The Journal of biological chemistry · 2012Article
- Ligand-gated ion channels: from genes to behaviour.The Journal of physiology · 2012Article
- The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6β22 and 6β2 GABA(A) receptor channel gating and expression.The Journal of physiology · 2011Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
The GABA(A) receptor mutation gamma(2)R43Q causes absence epilepsy in humans. Homology modeling suggests that gamma(2)Arg43, gamma(2)Glu178, and beta(2)Arg117 participate in a salt-bridge network linking the gamma(2) and beta(2) subunits. Here we show that several mutations at these locations exert similar long-distance effects on other intersubunit interfaces involved in GABA and benzodiazepine binding. These mutations alter GABA-evoked receptor kinetics by slowing deactivation, enhancing desensitization, or both. Kinetic modeling and nonstationary noise analysis for gamma(2)R43Q reveal that these effects are due to slowed GABA unbinding and slowed recovery from desensitization. Both gamma(2)R43Q and beta(2)R117K also speed diazepam dissociation from the receptor's benzodiazepine binding interface, as assayed by the rate of decay of diazepam-induced potentiation of GABA-evoked currents. These data demonstrate that gamma(2)Arg43 and beta(2)Arg117 similarly regulate the stability of both the GABA and benzodiazepine binding sites at the distant beta/alpha and alpha/gamma intersubunit interfaces, respectively. A simple explanation for these results is that gamma(2)Arg43 and beta(2)Arg117 participate in interactions between the gamma(2) and beta(2) subunits, disruptions of which alter the neighboring intersubunit binding sites in a similar fashion. In addition, gamma(2)Arg43 and gamma(2)Glu178 regulate desensitization, probably mediated within the transmembrane domains near the pore. Therefore, mutations at the gamma/beta intersubunit interface have specific long-distance effects that are propagated widely throughout the GABA(A) receptor protein.
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