EAAT1

EAAT1, also known as GLAST (glial high-affinity glutamate transporter), is a sodium-dependent excitatory amino acid transporter encoded by the SLC1A3 gene. It is a member of the SLC1 family and is primarily expressed in astrocytes throughout the central nervous system, with particularly high expression in the cerebellum and cortex. Its central role is to clear glutamate from the extracellular space after synaptic release, helping to terminate excitatory signals and prevent glutamate-induced excitotoxicity. This transporter also contributes to the regulation of ambient glutamate levels that influence synaptic plasticity and neuronal communication.

Mechanism and properties: EAAT1 co-transports glutamate with three Na+ ions and one H+ into the cell, while counter-transporting one K+ out, driven by the ionic gradients across the plasma membrane. In addition to its transport function, EAAT1 is associated with a chloride conductance that increases membrane permeability to Cl−, an activity that can modulate neuronal excitability in a manner not solely tied to substrate transport.

Structure and regulation: Each EAAT1 monomer contains a transport domain within a trimeric complex, and the transporter cycles between outward- and inward-facing conformations to move substrates. Expression and activity are regulated by neuronal activity, astrocyte signaling, and cellular energy status.

Clinical significance: Pathogenic variants in SLC1A3 cause episodic ataxia type 6 (EA6), a rare inherited movement disorder characterized by episodes of cerebellar dysfunction. Altered EAAT1 function has been investigated in migraine and epilepsy, among other conditions, though causal relationships remain under study. Animal models show that loss of EAAT1 raises extracellular glutamate and increases vulnerability to excitotoxic damage.

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