ArticleThe Journal of clinical investigation2022
Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function.
Article in The Journal of clinical investigation, 2022. 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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Who cites it
16 citing papers in PubMed, 21 citations in OpenAlex.
- Overactive EAAT1 ClActa neuropathologica communications · 2026Article
- Optimizing Antiseizure Candidate Compounds Using Deuterium Substitution.ACS central science · 2026Article
- Multimodal dynamics control activity of a glial glutamate transporter.bioRxiv : the preprint server for biology · 2026Article
- The Double-Edged Effect of Connexins and Pannexins of Glial Cells in Central and Peripheral Nervous System After Nerve Injury.Molecular neurobiology · 2025Review
- An integrated multi-omics analysis identifies novel regulators of circadian rhythm and sleep disruptions under unique light environment in Antarctica.Molecular psychiatry · 2025Article
- The severity of SLC1A2-associated neurodevelopmental disorders correlates with transporter dysfunction.EBioMedicine · 2025Article
- Computational Characterization of Membrane Proteins as Anticancer Targets: Current Challenges and Opportunities.International journal of molecular sciences · 2024Review
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- Pharmacological modulation of chloride channels as a therapeutic strategy for neurological disorders.Frontiers in physiology · 2023Review
- Molecular insights into disease-associated glutamate transporter (EAAT1 /Frontiers in molecular biosciences · 2023Article
- Characterizing unexpected interactions of a glutamine transporter inhibitor with members of the SLC1A transporter family.The Journal of biological chemistry · 2022Article
- Microscopic Characterization of the Chloride Permeation Pathway in the Human Excitatory Amino Acid Transporter 1 (EAAT1).ACS chemical neuroscience · 2022Article
- Glutamatergic system components as potential biomarkers and therapeutic targets in cancer in non-neural organs.Frontiers in endocrinology · 2022Review
- Urine metabolomics analysis of sleep quality in deep-underground miners: A pilot study.Frontiers in public health · 2022Article
- Structural and molecular determinants of glutamate transporter allosteric modulators.Molecular pharmacologyArticle
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory amino acid transporters (EAATs) regulate extracellular glutamate by transporting it into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs are also chloride (Cl-) channels, but the physiological role of Cl- conductance through EAATs is poorly understood. Mutations of human EAAT1 (hEAAT1) have been identified in patients with episodic ataxia type 6 (EA6). One mutation showed increased Cl- channel activity and decreased glutamate transport, but the relative contributions of each function of hEAAT1 to mechanisms underlying the pathology of EA6 remain unclear. Here we investigated the effects of 5 additional EA6-related mutations on hEAAT1 function in Xenopus laevis oocytes, and on CNS function in a Drosophila melanogaster model of locomotor behavior. Our results indicate that mutations resulting in decreased hEAAT1 Cl- channel activity but with functional glutamate transport can also contribute to the pathology of EA6, highlighting the importance of Cl- homeostasis in glial cells for proper CNS function. We also identified what we believe is a novel mechanism involving an ectopic sodium (Na+) leak conductance in glial cells. Together, these results strongly support the idea that EA6 is primarily an ion channelopathy of CNS glia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.