| Protein Name | Solute Carrier Family 6 Member 1 (GABA Transporter 1) |
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| Gene | [SLC6A1](/genes/slc6a1) |
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| UniProt ID | P30531 |
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| Protein Size | 599 amino acids (~63 kDa) |
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| Subcellular Localization | Plasma membrane; presynaptic terminals |
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| Protein Family | SLC6 family (Sodium:neurotransmitter symporters, SSS) |
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| PDB Structures | 6WE7, 5U75 |
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SLC6A1 (GABA Transporter 1, GAT-1) is a sodium-dependent GABA transporter that regulates GABA signaling in the brain by reuptaking GABA into neurons and glia. It plays critical roles in inhibitory neurotransmission and is implicated in epilepsy and other neurological disorders.
SLC6A1 has the classic SLC6 transporter fold:
- 12 Transmembrane Domains: Alpha-helices that form the translocation pathway
- N-terminal and C-terminal Intracellular Loops: Important for trafficking and regulation
- Sodium Binding Sites: Multiple Na+ binding sites required for transport
- GABA Binding Site: Central binding pocket that alternates between outward- and inward-facing conformations
- Chloride Ion Binding Site: Cl- ions are co-transported with GABA and Na+
The transporter operates via the alternating access mechanism, transitioning between outward-facing and inward-facing conformations.
GAT-1 performs essential functions in GABAergic signaling:
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GABA Reuptake: Clears GABA from the synaptic cleft after neurotransmission, terminating the signal[1].
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GABA Recycling: Transport GABA back into presynaptic neurons for reuse or into glial cells for metabolism.
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Maintenance of Inhibitory Tone: Precisely controls extracellular GABA levels to maintain proper inhibition.
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Presynaptic Regulation: Regulates presynaptic GABA release through transporter activity.
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Protection against Excitotoxicity: Prevents excessive extracellular GABA that could cause paradoxical excitation.
- GAT-1 dysfunction contributes to epilepsy pathogenesis
- Reduced GAT-1 function leads to impaired GABA clearance and hyperexcitability
- GAT-1 knockout mice exhibit spontaneous seizures
- Tiagabine (GAT-1 inhibitor) can cause seizures as side effect
- SLC6A1 mutations cause a spectrum of epileptic encephalopathies
- Affected individuals have myoclonic-astatic seizures
- Developmental delay and intellectual disability common
- Altered GAT-1 expression in AD brains may contribute to network dysfunction
- GABAergic dysfunction correlates with cognitive decline
- Targeting GAT-1 explored as therapeutic approach
- GAT-1 in basal ganglia regulates inhibitory output
- Modulation affects motor symptoms
- GAT-1 inhibitors explored as adjunct therapy
GAT-1 is a proven therapeutic target:
- Tiagabine: Selective GAT-1 inhibitor used as anticonvulsant
- Nirmezumab: Anti-GAT-1 antibody being investigated for epilepsy
- Small Molecule Modulators: GAT-1 enhancers for cognitive enhancement
Note: GAT-1 inhibitors must be used carefully as excessive GABA elevation can cause paradoxical effects.
SLC6A1 interacts with:
- GABA: Primary substrate
- Sodium (Na+): Required co-transport ion
- Chloride (Cl-): Co-transported ion
- Protein Kinases: PKC regulates transporter activity
- Neuronal Interactors: Synaptic scaffolding proteins for localization
- [1] GABA transporter function (Borden et al., 1994)