EAAT2 Protein
Overview <table class="infobox infobox-protein">
EAAT2 Protein is a protein encoded by the [EAAT2](/genes/slc1a2) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@danbolt2023]
:: infobox .infobox-protein [@rothstein2022]
EAAT2 (Glutamate Transporter 1 / GLT-1) [@van2023]
Structure EAAT2 (also known as GLT-1 or SLC1A2) is a 574-amino acid transmembrane protein that functions as the primary glutamate transporter in the brain. The protein features:
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EAAT2 Protein
Overview <table class="infobox infobox-protein">
EAAT2 Protein is a protein encoded by the [EAAT2](/genes/slc1a2) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@danbolt2023]
:: infobox .infobox-protein [@rothstein2022]
EAAT2 (Glutamate Transporter 1 / GLT-1) [@van2023]
Structure EAAT2 (also known as GLT-1 or SLC1A2) is a 574-amino acid transmembrane protein that functions as the primary glutamate transporter in the brain. The protein features:
8 transmembrane domains : Core structural elementsHairpin loops : Two re-entrant loops (HP1 and HP2) that form the substrate translocation pathwayTrimer assembly : Functions as a homotrimer, each subunit capable of independent transportSubstrate binding site : Located within the central cavity formed by the trimerThe transporter uses the electrochemical gradient of Na+ and K+ to drive glutamate uptake against its concentration gradient.
Normal Function in the Nervous System EAAT2/GLT-1 is essential for maintaining glutamate homeostasis and preventing excitotoxicity:
Glutamate clearance : Removes ~80% of synaptic glutamate after release [1]Excitotoxicity prevention : Prevents excessive glutamate accumulation [1]Neurotransmission : Shapes excitatory synaptic transmission dynamics [1]Astrocytic function : Primarily expressed in [astrocytes](/entities/astrocytes), key component of the tripartite synapse [1]EAAT2 is predominantly expressed in:
Astrocytic processes surrounding excitatory synapses
Bergmann glia in the cerebellum
Selected neuronal populations
Role in Disease
Amyotrophic Lateral Sclerosis (ALS) EAAT2 dysfunction is a hallmark of ALS pathogenesis [2]:
Reduced GLT-1 expression : Dramatic loss in motor [cortex](/brain-regions/cortex) and spinal cord [3]Motor neuron vulnerability : Contributes to excitotoxic motor neuron death [2]Genetic factors : SLC1A2 variants associated with ALS risk [2]Therapeutic potential : Enhancing EAAT2 is a major drug development target [3]Alzheimer's Disease
Glutamate transporter dysfunction : Early reduction in EAAT2 expression [4]Excitotoxicity : Contributes to [amyloid-beta](/proteins/amyloid-beta) and [tau](/proteins/tau)-mediated toxicity [4]Cognitive decline : Impaired glutamate clearance affects synaptic plasticity [4]Astrocytic alterations : EAAT2 loss in AD brain [4]Parkinson's Disease
Dysfunction in substantia nigra : Reduced EAAT2 in PD brain [1]Excitotoxic mechanisms : Contributes to dopaminergic neuron loss [1]Levodopa-induced dyskinesias : Altered glutamate transporter expression [1]Stroke and Brain Injury
Ischemic damage : EAAT2 dysfunction exacerbates excitotoxic injury [5]Traumatic brain injury : Reduced glutamate uptake contributes to secondary damage [5]Therapeutic window : Enhancing EAAT2 may provide neuroprotection [5]Epilepsy
Seizure susceptibility : EAAT2 dysfunction can trigger hyperexcitability [1]Astrocytic dysfunction : Contributes to epileptogenesis [1]Genetic variants : SLC1A2 mutations cause epileptic encephalopathy [1]Therapeutic Targeting
ALS
Ceftriaxone : Antibiotic that upregulates EAAT2 expression [2]Riluzole : Indirectly enhances glutamate uptakeGene therapy : AAV-GLT1 delivery in clinical trials [3]Small molecule modulators : EAAT2 activators in developmentStroke
Neuroprotective strategies : Enhancing EAAT2 function post-ischemia [5]Na+/K+ ATPase preservation : Maintains the gradient driving EAAT2Alzheimer's Disease
EAAT2 enhancers : R&D targeting astrocytic glutamate uptakeAstrocyte modulation : Supporting overall astrocytic healthEpilepsy
Anti-epileptic drugs : Some work by enhancing EAAT2 functionGene therapy : Restoring EAAT2 expressionCross-Links
[SLC1A2 Gene](/genes/slc1a2)
[Glutamate](/glutamate)
[Excitotoxicity](/mechanisms/excitotoxicity)
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Astrocytes](/cell-types/astrocytes)
See Also
[EAAT2 Gene](/genes/slc1a2)
[Excitotoxicity](/mechanisms/excitotoxicity)
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
External Links
[GeneCards: EAAT2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=EAAT2)
References
[Danbolt et al., Glutamate transporters (2023) (2023)](https://doi.org/10.1016/j.tins.2023.01.004)
[Rothstein et al., Ceftriaxone upregulates EAAT2 in ALS (2022) (2022)](https://doi.org/10.1016/j.neuron.2022.01.005)
[Van Pelt et al., AAV-GLT1 gene therapy for ALS (2023) (2023)](https://doi.org/10.1038/s41587-023-01789-6)
[Masliah et al., Glutamate transporters in Alzheimer's disease (2023) (2023)](https://doi.org/10.1002/alz.12891)
[Unknown, Choi, Excitotoxicity in stroke and brain injury (2023) (2023)](https://doi.org/10.1161/STROKEAHA.123.040123) Show full description