ArticleThe Journal of biological chemistry2013
Functional defects in the external and internal thin gates of the γ-aminobutyric acid (GABA) transporter GAT-1 can compensate each other.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 26 citations in OpenAlex.
- Structural and functional basis of antinociceptive action of χ-conotoxin AoIA at the noradrenaline transporter.Nature structural & molecular biology · 2026Article
- Pathogenic variants at the N-terminal arginine residue 44 disrupt human GABA transporter 1 function: insights fromFrontiers in pharmacology · 2025Article
- Experimental and Bioinformatic Insights into the Effects of Epileptogenic Variants on the Function and Trafficking of the GABA Transporter GAT-1.International journal of molecular sciences · 2023Article
- A comparative review on the well-studied GAT1 and the understudied BGT-1 in the brain.Frontiers in physiology · 2023Review
- Structural insights into GABA transport inhibition using an engineered neurotransmitter transporter.The EMBO journal · 2022Article
- Structural basis of GABA reuptake inhibition.Nature · 2022Article
- Article
- Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.Pharmacology & therapeutics · 2021Review
- Chloride-dependent conformational changes in the GlyT1 glycine transporter.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- The Amino Terminus of LeuT Changes Conformation in an Environment Sensitive Manner.Neurochemical research · 2020Article
- Serotonin transport in the 21st century.The Journal of general physiology · 2019Review
- Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- An Extra Amino Acid Residue in Transmembrane Domain 10 of the γ-Aminobutyric Acid (GABA) Transporter GAT-1 Is Required for Efficient Ion-coupled Transport.The Journal of biological chemistry · 2017Article
- Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.American journal of human genetics · 2015Article
- A conserved salt bridge between transmembrane segments 1 and 10 constitutes an extracellular gate in the dopamine transporter.The Journal of biological chemistry · 2014Article
- GABA and Glutamate Transporters in Brain.Frontiers in endocrinology · 2013Review
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2 authors.
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Abstract
The GABA transporter GAT-1 belongs to the neurotransmitter:sodium:symporters which are crucial for synaptic transmission. GAT-1 mediates electrogenic transport of GABA together with sodium and chloride. Structure-function studies indicate that the bacterial homologue LeuT, which possess extra- and intracellular thin gates, is an excellent model for this class of neurotransmitter transporters. We recently showed that a conserved aspartate residue of GAT-1, Asp-451, whose LeuT equivalent participates in its thin extracellular gate, is functionally irreplaceable in GAT-1. Only the D451E mutant exhibited residual transport activity but with an elevated apparent sodium affinity as a consequence of an increased proportion of outward-facing transporters. Because during transport the opening and closing of external and internal gates should be tightly coupled, we have addressed the question of whether mutations of the intracellular thin gate residues Arg-44 and Asp-410 can compensate for the effects of their extracellular counterparts. Mutation of Asp-410 to glutamate resulted in impaired transport activity and a reduced apparent affinity for sodium. However, the transport activity of the double mutant D410E/D451E was increased by approximately 10-fold of that of each of the single mutants. Similar compensatory effects were also seen when other combinations of intra- and extracellular thin gate mutants were analyzed. Moreover, the introduction of D410E into the D451E background resulted in lower apparent sodium affinity than that of D451E alone. Our results indicate that a functional interaction of the external and internal gates of GAT-1 is essential for transport.
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