ArticleThe Journal of biological chemistry2014
Proteome analysis and conditional deletion of the EAAT2 glutamate transporter provide evidence against a role of EAAT2 in pancreatic insulin secretion in mice.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 50 citations in OpenAlex.
- Glutamatergic dysfunction of astrocytes in paraventricular nucleus of thalamus contributes to adult anxiety susceptibility in adolescent ethanol exposed mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Multi-omic human pancreatic islet endoplasmic reticulum and cytokine stress response mapping provides type 2 diabetes genetic insights.Cell metabolism · 2024Article
- Hyperglycemia impairs EAAT2 glutamate transporter trafficking and glutamate clearance in islets of Langerhans: implications for type 2 diabetes pathogenesis and treatment.American journal of physiology. Endocrinology and metabolism · 2024Article
- Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review).Biomedical reports · 2024Review
- Still in Search for an EAAT Activator: GT949 Does Not Activate EAAT2, nor EAAT3 in Impedance and Radioligand Uptake Assays.ACS chemical neuroscience · 2024Article
- Transporter-Mediated Drug Delivery.Molecules (Basel, Switzerland) · 2023Review
- Metabolism-secretion coupling in glucose-stimulated insulin secretion.Diabetology international · 2022Review
- Comprehensive Analysis of Potential Correlation Between Solute Carrier 1A (SLC1A) Family and Lung Adenocarcinoma.International journal of general medicine · 2022Article
- Potential Therapeutic Targeting Neurotransmitter Receptors in Diabetes.Frontiers in endocrinology · 2022Review
- Alpha-Asaronol Alleviates Dysmyelination by Enhancing Glutamate Transport Through the Activation of PPARγ-GLT-1 Signaling in Hypoxia-Ischemia Neonatal Rats.Frontiers in pharmacology · 2022Article
- Reconstitution of GABA, Glycine and Glutamate Transporters.Neurochemical research · 2022Review
- Article
- Factors Influencing Mitochondrial Function as a Key Mediator of Glucose-Induced Insulin Release: Highlighting Nicotinamide Nucleotide Transhydrogenase.International journal of molecular and cellular medicine · 2020Review
- Astrocytes and Glutamine Synthetase in Epileptogenesis.Journal of neuroscience research · 2019Review
- Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration.Neurochemistry international · 2019Article
- Glutamate Transport and Preterm Brain Injury.Frontiers in physiology · 2019Review
- Expression of Glutamate Transporters in Mouse Liver, Kidney, and Intestine.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2018Article
- CD44 variant inhibits insulin secretion in pancreatic β cells by attenuating LAT1-mediated amino acid uptake.Scientific reports · 2018Article
- Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men.Physiological reviews · 2018Review
- Orexin-A promotes Glu uptake by OX1R/PKCα/ERK1/2/GLT-1 pathway in astrocytes and protects co-cultured astrocytes and neurons against apoptosis in anoxia/hypoglycemic injury in vitro.Molecular and cellular biochemistry · 2017Article
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
Islet function is incompletely understood in part because key steps in glutamate handling remain undetermined. The glutamate (excitatory amino acid) transporter 2 (EAAT2; Slc1a2) has been hypothesized to (a) provide islet cells with glutamate, (b) protect islet cells against high extracellular glutamate concentrations, (c) mediate glutamate release, or (d) control the pH inside insulin secretory granules. Here we floxed the EAAT2 gene to produce the first conditional EAAT2 knock-out mice. Crossing with Nestin-cyclization recombinase (Cre) eliminated EAAT2 from the brain, resulting in epilepsy and premature death, confirming the importance of EAAT2 for brain function and validating the genetic construction. Crossing with insulin-Cre lines (RIP-Cre and IPF1-Cre) to obtain pancreas-selective deletion did not appear to affect survival, growth, glucose tolerance, or β-cell number. We found (using TaqMan RT-PCR, immunoblotting, immunocytochemistry, and proteome analysis) that the EAAT2 levels were too low to support any of the four hypothesized functions. The proteome analysis detected more than 7,000 islet proteins of which more than 100 were transporters. Although mitochondrial glutamate transporters and transporters for neutral amino acids were present at high levels, all other transporters with known ability to transport glutamate were strikingly absent. Glutamate-metabolizing enzymes were abundant. The level of glutamine synthetase was 2 orders of magnitude higher than that of glutaminase. Taken together this suggests that the uptake of glutamate by islets from the extracellular fluid is insignificant and that glutamate is intracellularly produced. Glutamine synthetase may be more important for islets than assumed previously.
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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.