EAAT3

The neuronal excitatory amino acid transporter 3 (EAAT3, also known as EAAC1) mediates Na⁺-dependent uptake of glutamate and the uncharged amino acid L-cysteine, which is essential for neuronal glutathione synthesis and prevention of oxidative stress^[1][2][3]. Mechanistically, EAAT3 exhibits a high affinity for cysteine via thiolate formation in its binding site, allowing predominantly unidirectional transport without significant substrate release^[1]. EAAT3 contributes to maintaining low extracellular glutamate concentrations at the synapse, thereby regulating excitatory neurotransmission and limiting excitotoxicity^[3][4]. In disease models, EAAT3 expression is altered in the striatum of schizophrenia and bipolar disorder, implicating neuronal glutamate transport dysfunction in psychiatric pathology^[5][6]. Compared with related isoforms, EAAT3 uniquely transports cysteine efficiently, whereas glial transporters EAAT1 and EAAT2 exhibit negligible cysteine transport^[1][2]. EAAT3 also displays partial sensitivity to membrane lipid composition, associating with cholesterol-rich lipid rafts, which influences transporter localization and function^[7]. Pharmacologically, EAAT3 can be inhibited by broad-spectrum EAAT inhibitors such as threo-beta-hydroxyaspartate, though selective activation remains challenging due to the scarcity of effective agonists^[8][9][10]. Therefore, EAAT3 serves as a critical regulator of neuronal redox balance and glutamatergic signaling, providing a distinct target for studies of oxidative stress, synaptic modulation, and neuropsychiatric disease mechanisms^[1][2][3][5].