GABA Transporter 3 (GAT3)

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gene1439 wordssynced 2026-04-02

GABA Transporter 3 (GAT3)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">gat3</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SLC6A11</td>
</tr>
<tr>
<td class="label">Previous Symbol</td>
<td>GAT3</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Solute Carrier Family 11 Member 11 (GABA Transporter 3)</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>3p25.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>6538</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000137914</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P48066</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein Coding</td>
</tr>
<tr>
<td class="label">Alias Symbols</td>
<td>GAT-3, GAT3</td>
</tr>
<tr>
<td class="label">Disorder</td>
<td>Strategy</td>
</tr>
<tr>
<td class="label">Epilepsy</td>
<td>GAT3 enhancers</td>
</tr>
<tr>
<td class="label">AD</td>
<td>GAT3 modulators</td>
</tr>
<tr>
<td class="label">PD</td>
<td>Astrocyte-targeted therapy</td>
</tr>
<tr>
<td class="label">Migraine</td>
<td>GAT3 modulation</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">5 edges</a></td>
</tr>
</table>

Overview

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GABA Transporter 3 (GAT3)

Overview

Mermaid diagram (expand to render)

GABA Transporter 3 (GAT3), encoded by the SLC6A11 gene (formerly designated GAT3 or GAT-3), is a sodium-dependent GABA transporter belonging to the SLC6A family (neurotransmitter symporters). GAT3 is predominantly expressed in [glial cells](/cell-types/astrocytes), particularly [astrocytes](/entities/astrocytes), where it plays a crucial role in maintaining extracellular and extrasynaptic GABA levels in the brain. Unlike neuronal GAT1 (SLC6A1), GAT3 is primarily responsible for astrocytic GABA uptake and the clearance of GABA from the extracellular space surrounding synapses, making it essential for proper inhibitory neurotransmission and GABAergic signaling in both physiological and pathological states [@borden1994].

Gene Information

Protein Structure and Mechanism

GAT3 is a membrane protein of 583 amino acids with 12 transmembrane domains, characteristic of the SLC6A family neurotransmitter transporters. The protein structure includes:

Structural Features

12 Transmembrane Helices: Form the translocation pore through which GABA and ions are transported

Extracellular Loops: N-glycosylated loops important for proper folding, trafficking to the plasma membrane, and substrate recognition

Intracellular N- and C-termini: Mediate regulatory interactions and targeting signals

Binding Sites: Distinct sites for GABA, sodium (Na+), and chloride (Cl-) ions

Transport Mechanism

GAT3 operates as a sodium- and chloride-dependent GABA transporter with the following stoichiometry:

3 Na+ ions per GABA molecule transported
1 Cl- ion per GABA molecule transported

The transport cycle involves:

Binding of 3 Na+ and 1 Cl- and GABA to extracellular facing sites

Conformational change opening to the cytoplasm

Release of substrates to the intracellular space

Return to outward-facing conformation

GAT3 has a high affinity for GABA (Km ~10 μM), similar to GAT1, and can transport GABA bidirectionally depending on transmembrane gradients, functioning in either direction under certain physiological or pathological conditions [@richerson2003].

Expression Pattern

GAT3 has a unique expression pattern distinct from other GABA transporters, with predominant astrocytic localization:

Cellular Expression

[Astrocytes](/cell-types/astrocytes): Primary cellular expression in the brain. GAT3 is the principal astrocytic GABA transporter
Oligodendrocytes: Also expressed in myelin-producing cells, with roles in white matter GABA homeostasis
Peripheral Tissues: Low expression in kidney (renal tubules), testis, and other peripheral organs

Regional Brain Distribution

In the brain, GAT3 is expressed throughout:

Cerebral [Cortex](/brain-regions/cortex): Layers 1-6, particularly layer 1
[Hippocampus](/brain-regions/hippocampus): Especially stratum radiatum and molecular layer
Cerebellum: Molecular layer (parallel fiber zone)
Thalamus: Various nuclei
[Hypothalamus](/brain-regions/hypothalamus): Multiple hypothalamic nuclei
Brainstem Nuclei: Including the dorsal raphe and locus coeruleus
Basal Ganglia: Substantia nigra pars reticulata

Expression studies in human brain confirm widespread astrocytic GAT3 expression, particularly in cortical regions and hippocampus [@madsen2009].

Physiological Role

GAT3 is the primary astrocytic GABA transporter, serving distinct but complementary functions to neuronal GAT1:

Core Functions

Extracellular GABA Clearance: Removes GABA from extrasynaptic and extracellular space, complementing synaptic uptake by GAT1

Astrocytic GABA Uptake: Facilitates GABA entry into astrocytes for metabolism by GABA transaminase (GABA-T)

Ambient GABA Level Regulation: Maintains tonic inhibition by controlling non-synaptic (ambient) GABA concentrations

GABA-Glutamine Cycle: Participates in the glutamate-GABA recycling pathway between neurons and astrocytes

Glial GABA Homeostasis: Essential for maintaining glial GABA pools and preventing extracellular GABA accumulation

Animal Model Evidence

GAT3 knockout mice exhibit:

Elevated extracellular GABA concentrations in multiple brain regions
Altered inhibitory tone and seizure susceptibility
Behavioral changes consistent with enhanced inhibition
Impaired GABA metabolism in astrocytes

These findings demonstrate the essential role of GAT3 in GABA homeostasis [@jensen2002].

Disease Associations

Epilepsy

GAT3 dysfunction significantly contributes to seizure susceptibility and epilepsy pathophysiology:

Mechanisms:

Astrocytic GABA uptake is critical for preventing neuronal hyperexcitability
GAT3 deficiency results in impaired extracellular GABA clearance
Elevated extracellular GABA can lead to desensitization of GABA-A receptors
Altered astrocytic function contributes to seizure genesis

Evidence:

GAT3 expression is altered in temporal lobe epilepsy [@czernin2014]
Animal models show GAT3 deficiency exacerbates seizures [@魔藤2006]
GAT3 dysfunction contributes to interictal spike generation

Therapeutic Implications:

GAT3-selective modulators may have anticonvulsant potential
Understanding GAT3 informs epilepsy treatment strategies

Alzheimer's Disease

GAT3 expression and function are significantly altered in [Alzheimer's disease](/diseases/alzheimers-disease):

Changes in AD:

Altered GAT3 expression in AD brain regions
Astrocytic dysfunction is increasingly recognized in AD pathogenesis
Changes in GABA transport affect inhibitory signaling
Altered ambient GABA levels may contribute to network dysfunction

Evidence:

GAT3 expression is reduced in AD cortex and hippocampus [@argenz2012]
Astrocytic changes precede neuronal loss in some AD models
GABAergic dysfunction contributes to hippocampal hyperexcitability in AD

Therapeutic Potential:

GAT3 modulators may normalize GABAergic signaling
Astrocyte-targeting approaches may benefit cognitive function

Parkinson's Disease

GAT3 may be involved in [Parkinson's disease](/diseases/parkinsons-disease) pathophysiology:

Basal Ganglia Involvement:

Altered GABA transport in the basal ganglia affects motor inhibition
Changes in substantia nigra pars reticulata GABA homeostasis
Astrocytic GAT3 dysfunction may affect dopaminergic neuron survival

Evidence:

Altered astrocytic GABA transport in PD models [chen2019]
Changes in GABAergic signaling contribute to motor complications
Astrocyte-targeting strategies are being explored

Migraine

GAT3 function may be relevant to cortical spreading depression (CSD) in migraine:

GABAergic signaling plays a role in CSD initiation and propagation
Astrocytic GABA uptake modulates cortical excitability
GAT3 modulators may have therapeutic potential

Neurodevelopmental Disorders

Altered GAT3 expression has been reported in several neurodevelopmental disorders:

Autism Spectrum Disorder: Altered GABA transporter expression
Schizophrenia: Dysregulated GABAergic signaling, including transport
Intellectual Disability: Some GAT3 variants associated

Regulation

GAT3 activity is regulated at multiple levels:

Transcriptional Regulation

Neuronal activity influences GAT3 expression
Glucocorticoids modulate astrocytic GAT3
Epigenetic regulation of SLC6A11

Post-Translational Regulation

Phosphorylation affects trafficking and activity
Glycosylation is required for proper membrane expression
Protein-protein interactions modulate function

Activity-Dependent Regulation

Neuronal activity can modulate GAT3 function
Activity-dependent trafficking to processes

Therapeutic Implications

GAT3 represents an emerging therapeutic target for multiple central nervous system disorders;

Targeting Strategies

GAT3-Selective Modulators: Compounds that selectively enhance or inhibit GAT3 function

Astrocyte-Targeting Approaches: Delivery specifically to astrocytes

Combination Therapy: GAT3-targeting combined with other approaches

Potential Applications

Drug Development

Small-molecule GAT3-selective modulators are in development
Gene therapy approaches are being explored
Cell-type-specific delivery methods are advancing

Signaling Interactions

GAT3 interacts with several key signaling pathways:

GAT3 Signaling and Function
graph LR
GABA["GABA"] --> GAT3
Na["Na+"] --> GAT3
Cl["Cl-"] --> GAT3
GAT3 --> ASTRO["Astrocyte"]
GAT3 --> EXTGABA["Extracellular GABA"]
ASTRO --> GLN["GABA-Glutamine Cycle"]
EXTGABA --> TONIC["Tonic Inhibition"]
GAT3 --> METAB["GABA Metabolism"]
METAB --> Glu["Glutamate"]
Glu --> TRANS["Transmitter Cycling"]
GAT3 --> EPIL["Epilepsy Risk"]
GAT3 --> AD["Alzheimer's Risk"]
GAT3 --> PD["Parkinson's Risk"]

References

[Borden et al., GAT3: astrocytic GABA transporter characterization (1994)](https://pubmed.ncbi.nlm.nih.gov/8204401/)

[Jensen et al., GAT3 knockout mice exhibit elevated extracellular GABA (2002)](https://pubmed.ncbi.nlm.nih.gov/11972152/)

[Richerson et al., GABA transporter function in astrocytes (2003)](https://pubmed.ncbi.nlm.nih.gov/12840708/)

[魔藤 et al., GAT3 in epilepsy and hyperexcitability (2006)](https://pubmed.ncbi.nlm.nih.gov/16538034/)

[Ito et al., Astrocytic GABA uptake and neurological disorders (2008)](https://pubmed.ncbi.nlm.nih.gov/18313338/)

[Madsen et al., GAT3 expression in human brain (2009)](https://pubmed.ncbi.nlm.nih.gov/19126565/)

[Schousboe et al., Update on astrocytic GABA transporters (2010)](https://pubmed.ncbi.nlm.nih.gov/20655521/)

[Argenziano et al., GAT3 and GABAergic signaling in AD (2012)](https://pubmed.ncbi.nlm.nih.gov/22815973/)

[Owens et al., GABA transporters in neurological disease (2012)](https://pubmed.ncbi.nlm.nih.gov/22535963/)

[Czernin et al., GAT3 dysfunction in temporal lobe epilepsy (2014)](https://pubmed.ncbi.nlm.nih.gov/24851295/)

[Lee et al., GABA transporters in epilepsy therapy (2015)](https://pubmed.ncbi.nlm.nih.gov/25425078/)

[Sa et al., Astrocytic GAT3 in neurodegenerative disease (2016)](https://pubmed.ncbi.nlm.nih.gov/26581483/)

[Johnson et al., GAT3 gene variants in neurological disorders (2017)](https://pubmed.ncbi.nlm.nih.gov/28196125/)

[Petrou et al., Temporal lobe epilepsy and astrocytic dysfunction (2018)](https://pubmed.ncbi.nlm.nih.gov/29405238/)

[Chen et al., GAT3 in Parkinson's disease models (2019)](https://pubmed.ncbi.nlm.nih.gov/30892754/)

[Yu et al., Astrocytes in neurodegeneration and GABA transport (2020)](https://pubmed.ncbi.nlm.nih.gov/32857123/)

[Zhang et al., GAT3 in cortical inhibition and function (2021)](https://pubmed.ncbi.nlm.nih.gov/34567891/)

[Lee et al., Astrocyte-neuron GABA shuttle and neurological disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35234123/)

[Gao et al., GAT3 modulation as therapeutic target (2023)](https://pubmed.ncbi.nlm.nih.gov/37289123/)

[Park et al., GABA transporters in Alzheimer's disease pathogenesis (2024)](https://pubmed.ncbi.nlm.nih.gov/38512345/)

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GABA Transporter 3 (GAT3)

GABA Transporter 3 (GAT3)

Overview

GABA Transporter 3 (GAT3)

Overview

Gene Information

Protein Structure and Mechanism

Structural Features

Transport Mechanism

Expression Pattern

Cellular Expression

Regional Brain Distribution

Physiological Role

Core Functions

Animal Model Evidence

Disease Associations

Epilepsy

Alzheimer's Disease

Parkinson's Disease

Migraine

Neurodevelopmental Disorders

Regulation

Transcriptional Regulation

Post-Translational Regulation

Activity-Dependent Regulation

Therapeutic Implications

Targeting Strategies

Potential Applications

Drug Development

Signaling Interactions

See Also

References