GLT1

GLT-1, also called EAAT2 (excitatory amino acid transporter 2), is a high-affinity glutamate transporter primarily expressed in astrocytes in the mammalian central nervous system. In rodents the transporter is encoded by Slc1a2; in humans the ortholog is SLC1A2. It plays a central role in clearing extracellular glutamate from the synaptic cleft, helping terminate excitatory signaling and protect neurons from excitotoxicity.

Mechanistically, GLT-1 is a Na+- and H+-coupled transporter with K+ counter-transport. It co-transports one glutamate molecule with three Na+ and one H+ into the cell and moves K+ out, generating a net inward current that drives uptake against glutamate concentration gradients.

GLT-1 is most abundant in astrocytes throughout the cortex and hippocampus, with regionally variable expression. Its activity is regulated by neuronal activity, cytokines, and transcriptional control; inflammation and ischemia can reduce GLT-1 function, while certain stimuli upregulate its expression.

Dysfunction or loss of GLT-1 is associated with various CNS disorders characterized by glutamatergic excitotoxicity, including stroke, traumatic brain injury, ALS, Alzheimer's disease, and epilepsy. In mice, GLT-1 deficiency leads to severe neurotoxicity and early mortality, underscoring its essential neuroprotective role.

From a therapeutic standpoint, boosting GLT-1/EAAT2 activity is an area of interest. In preclinical models, beta-lactam antibiotics such as ceftriaxone increase EAAT2 expression and glutamate uptake; research continues into safe, targeted means to enhance GLT-1 function and reduce excitotoxic injury. Specific pharmacological inhibitors of GLT-1 (for research) include dihydrokainic acid and DL-threo-beta-benzyloxyaspartate.