ArticleThe Journal of biological chemistry2010
GABA(A) receptor alpha1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA(A) receptors.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 53 citations in OpenAlex.
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- Improving Proteostasis of Trafficking-Deficient GABAACS chemical neuroscience · 2025Article
- Polymorphic variants in GABA-A receptor and their association with epilepsy and drug resistance: A North Indian cohort study.World journal of psychiatry · 2025Article
- Clinical and functional characterization of the GABRB3 p.Met80Val variant in early-onset epilepsy with long-term follow-up.Italian journal of pediatrics · 2025Article
- Genetic Animal Models of Idiopathic Generalized Epilepsies: What Can We Learn from Them?Biomedicines · 2025Review
- Benzodiazepine-resistant epilepsy: unraveling molecular mechanisms and developing multimodal therapeutic strategies.Frontiers in neurology · 2025Review
- Pathogenic variants of human GABRA1 gene associated with epilepsy: A computational approach.Heliyon · 2023Article
- Genetic mechanisms in generalized epilepsies.Acta epileptologica · 2023Review
- Pharmacological activation of ATF6 remodels the proteostasis network to rescue pathogenic GABACell & bioscience · 2022Article
- Disruption of the Ubiquitin-Proteasome System and Elevated Endoplasmic Reticulum Stress in Epilepsy.Biomedicines · 2022Review
- Distinct Functional Alterations and Therapeutic Options of Two Pathological De Novo Variants of the T292 Residue of GABRA1 Identified in Children with Epileptic Encephalopathy and Neurodevelopmental Disorders.International journal of molecular sciences · 2022Article
- Proteostasis Regulators Restore Function of Epilepsy-Associated GABACell chemical biology · 2021Article
- Genetic Landscape of Common Epilepsies: Advancing towards Precision in Treatment.International journal of molecular sciences · 2020Review
- Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy.Frontiers in cellular neuroscience · 2019Review
- Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy.The Journal of pharmacology and experimental therapeutics · 2018Review
- Remodeling the endoplasmic reticulum proteostasis network restores proteostasis of pathogenic GABAA receptors.PloS one · 2018Article
- γ2 GABAFrontiers in cellular neuroscience · 2018Review
- AJournal of medical genetics · 2017Article
- Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation.The Journal of biological chemistry · 2016Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
A GABA(A) receptor (GABA(A)R) alpha1 subunit mutation, A322D (AD), causes an autosomal dominant form of juvenile myoclonic epilepsy (ADJME). Previous studies demonstrated that the mutation caused alpha1(AD) subunit misfolding and rapid degradation, reducing its total and surface expression substantially. Here, we determined the effects of the residual alpha1(AD) subunit expression on wild type GABA(A)R expression to determine whether the AD mutation conferred a dominant negative effect. We found that although the alpha1(AD) subunit did not substitute for wild type alpha1 subunits on the cell surface, it reduced the surface expression of alpha1beta2gamma2 and alpha3beta2gamma2 receptors by associating with the wild type subunits within the endoplasmic reticulum and preventing them from trafficking to the cell surface. The alpha1(AD) subunit reduced surface expression of alpha3beta2gamma2 receptors by a greater amount than alpha1beta2gamma2 receptors, thus altering cell surface GABA(A)R composition. When transfected into cultured cortical neurons, the alpha1(AD) subunit altered the time course of miniature inhibitory postsynaptic current kinetics and reduced miniature inhibitory postsynaptic current amplitudes. These findings demonstrated that, in addition to causing a heterozygous loss of function of alpha1(AD) subunits, this epilepsy mutation also elicited a modest dominant negative effect that likely shapes the epilepsy phenotype.
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