EAAT2 Protein is a protein encoded by the EAAT2 gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
:: infobox .infobox-protein
EAAT2 (Glutamate Transporter 1 / GLT-1)
: -
; Gene
: EAAT2 (SLC1A2)
; UniProt ID
: P43005
; PDB Structures
: 5LLI, 5LLM, 6GTC
; Molecular Weight
: ~65 kDa (human)
; Subcellular Localization
: Plasma membrane, astrocytic processes ensheathing synapses
; Protein Family
: Excitatory amino acid transporter (EAAT) family
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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 elements
- Hairpin loops: Two re-entrant loops (HP1 and HP2) that form the substrate translocation pathway
- Trimer assembly: Functions as a homotrimer, each subunit capable of independent transport
- Substrate binding site: Located within the central cavity formed by the trimer
The transporter uses the electrochemical gradient of Na+ and K+ to drive glutamate uptake against its concentration gradient.
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, 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
EAAT2 dysfunction is a hallmark of ALS pathogenesis [2]:
- Reduced GLT-1 expression: Dramatic loss in motor 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]
- Glutamate transporter dysfunction: Early reduction in EAAT2 expression [4]
- Excitotoxicity: Contributes to amyloid-beta and tau-mediated toxicity [4]
- Cognitive decline: Impaired glutamate clearance affects synaptic plasticity [4]
- Astrocytic alterations: EAAT2 loss in AD brain [4]
- 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]
- Seizure susceptibility: EAAT2 dysfunction can trigger hyperexcitability [1]
- Astrocytic dysfunction: Contributes to epileptogenesis [1]
- Genetic variants: SLC1A2 mutations cause epileptic encephalopathy [1]
- Ceftriaxone: Antibiotic that upregulates EAAT2 expression [2]
- Riluzole: Indirectly enhances glutamate uptake
- Gene therapy: AAV-GLT1 delivery in clinical trials [3]
- Small molecule modulators: EAAT2 activators in development
- Neuroprotective strategies: Enhancing EAAT2 function post-ischemia [5]
- Na+/K+ ATPase preservation: Maintains the gradient driving EAAT2
- EAAT2 enhancers: R&D targeting astrocytic glutamate uptake
- Astrocyte modulation: Supporting overall astrocytic health
- Anti-epileptic drugs: Some work by enhancing EAAT2 function
- Gene therapy: Restoring EAAT2 expression