Sodium- and chloride-dependent GABA transporter 3 (GAT-3) (GAT-3)

Human GABA transporter 3 (hGAT-3), encoded by the SLC6A11 gene, is a sodium- and chloride-dependent symporter primarily localized in astrocytes within the central nervous system [2, 7]. Its primary biological role is the reuptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) from the synaptic cleft, which terminates GABAergic signaling and regulates extrasynaptic GABA concentrations [1, 4]. By clearing GABA from the extracellular space, hGAT-3 plays a critical role in maintaining the balance between excitatory and inhibitory neurotransmission [5, 9]. Dysregulation or deficiency of hGAT-3 is implicated in several neurological and psychiatric conditions, including epilepsy, Alzheimer's disease, and alcohol dependence [6, 11, 13]. Pharmacological inhibition of hGAT-3 is a therapeutic strategy aimed at elevating extracellular GABA levels to enhance inhibitory tone, offering a distinct mechanism from GAT-1 inhibitors like tiagabine [1, 15]. While selective inhibitors such as (S)-SNAP-5114 and the more recent SR-THAP have been developed for research, none have yet reached clinical translation due to challenges in potency, selectivity, and pharmacokinetic properties [3, 6]. Targeting hGAT-3 also influences astrocytic GABA metabolism, potentially providing neuroprotective effects in conditions like stroke [6].

Other names

SLC6A11 [2, 11]GAT3 [7, 11]Solute carrier family 6 member 11 [2, 11]GABA transporter 3 [7, 11]GAT4 [7]

Inhibition of GABA reuptake from the synaptic cleft into astrocytes, leading to increased extracellular GABA levels and enhanced inhibitory neurotransmission [1, 4, 5, 6].