GAT1

GAT-1, or GABA transporter 1, is a high-affinity membrane transporter that reuptakes gamma-aminobutyric acid (GABA) from the synaptic cleft and surrounding extracellular space, terminating inhibitory signaling in the central nervous system. It is a member of the solute carrier 6 (SLC6) family of sodium- and chloride-dependent transporters. GAT-1 is encoded by the SLC6A1 gene and is expressed predominantly in neurons throughout the brain, with notable expression in forebrain regions, as well as on astrocytes in certain contexts.

Molecular characteristics include the fact that the protein spans the membrane 12 times and localizes to the plasma membrane. It uses sodium and chloride gradients to drive the uptake of GABA into cells, thereby regulating extracellular GABA concentration and both phasic and tonic inhibition.

Physiological and pharmacological roles of GAT-1 involve modulation of inhibitory synaptic transmission and neuronal excitability through control of GABA availability. GAT-1 activity influences GABA spillover and tonic inhibition in various neural circuits, contributing to the balance of excitation and inhibition in the CNS.

Clinical relevance centers on the use and study of GAT-1 inhibitors. Tiagabine is a clinically approved GAT-1 inhibitor with anticonvulsant effects due to increased extracellular GABA. Other GAT-1 selective inhibitors, such as SKF-89976-A, are used mainly in research settings. Variants in the SLC6A1 gene have been associated with neurodevelopmental disorders and epilepsy in some individuals, highlighting the transporter’s role in CNS function and disease.