SLC6A13 Gene

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gene1602 wordssynced 2026-04-02

SLC6A13 Gene

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SLC6A13 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">slc6a13</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SLC6A13</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Solute Carrier Family 6 Member 13 (GABA Transporter 2, GAT2)</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>12p13.33</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>6404</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>607469</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000110851</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9NPD8</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>572 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~63 kDa</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Epilepsy, Pain Disorders, Kidney Disease, Retinal Degeneration</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Relative Affinity</td>
</tr>
<tr>
<td class="label">GABA</td>
<td>Highest</td>
</tr>
<tr>
<td class="label">Beta-alanine</td>
<td>High</td>
</tr>
<tr>
<td class="label">Taurine</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Di-aminobutyrate</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Cerebral Cortex</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Basal Ganglia</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Spinal Cord</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>High</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>High</td>
</tr>
<tr>
<td class="label">Retina</td>
<td>High</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Testis</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Pancreas</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Agent</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Tiagabine</td>
<td>GAT1</td>
</tr>
<tr>
<td class="label">EF150227</td>
<td>GAT3</td>
</tr>
<tr>
<td class="label">NNC-711</td>
<td>GAT1/3</td>
</tr>
<tr>
<td class="label">SNAP-5114</td>
<td>GAT3</td>
</tr>
</table>

Introduction

The SLC6A13 gene (Solute Carrier Family 6 Member 13), also known as GABA Transporter 2 (GAT2), encodes a membrane transport protein responsible for the uptake of gamma-aminobutyric acid (GABA) from the extracellular space. Unlike the neuronal GAT1 (SLC6A1), GAT2 exhibits a broader expression pattern that includes both astrocytes in the central nervous system and various peripheral tissues, making it unique among the human GABA transporters. This dual localization suggests distinct physiological roles in both CNS homeostasis and peripheral organ function, with implications for neurological diseases, pain modulation, and systemic GABA metabolism [1].

GABA transporters are essential for terminating GABAergic signaling and maintaining neurotransmitter homeostasis. The four known human GABA transporters—GAT1 (SLC6A1), GAT2 (SLC6A13), GAT3 (SLC6A11), and GAT4 (SLC6A12)—each have distinct expression patterns and pharmacological properties. GAT2 is unique for its expression in both brain astrocytes and peripheral tissues including kidney, liver, and retina, suggesting roles beyond simple neurotransmitter clearance [2].

Gene Overview

Protein Structure and Function

Structural Organization

The SLC6A13 protein belongs to the SLC6 family of sodium-dependent neurotransmitter transporters, which share a common 12-transmembrane domain architecture. Key structural features include:

N-terminal extracellular domain: Contains conserved cysteine residues that form disulfide bonds critical for protein folding and stability. This domain also contributes to substrate recognition.

Transmembrane domains: The 12 transmembrane helices (TM1-TM12) form the central pore. The substrate binding site is located within these domains, with critical residues determining GABA specificity and inhibitor sensitivity.

Intracellular regulatory domains: The intracellular loops between TM6-TM7 and TM8-TM9 contain phosphorylation sites and trafficking signals that regulate transporter activity and membrane localization [3].

C-terminal cytoplasmic domain: Contains protein interaction motifs and regulatory sequences.

Transport Mechanism

GAT2 operates through sodium-coupled secondary active transport [4]:

Sodium binding: Two sodium ions bind to the transporter

Conformational change: The transporter undergoes a conformational change

GABA release: GABA is released into the intracellular space

Reset: The transporter returns to its outward-facing conformation

The stoichiometry is typically 2 Na+:1 GABA, allowing efficient uptake against concentration gradients.

Substrate Specificity

GAT2 exhibits specificity for:

Expression Pattern

Central Nervous System

In the brain, GAT2 is expressed primarily in astrocytes but at lower levels than GAT3 (SLC6A11) [5]:

Peripheral Tissues

GAT2 shows high expression in peripheral organs [6]:

The peripheral expression of GAT2 distinguishes it from other GABA transporters and suggests specialized functions beyond CNS neurotransmission.

Physiological Functions

CNS Functions

In the brain, GAT2 contributes to [7]:

GABA clearance: Removes GABA from the extracellular space following synaptic release, though less efficiently than GAT1.

Tonic inhibition: Helps maintain ambient GABA levels that regulate extrasynaptic GABA-A receptors.

Astrocytic function: Contributes to astrocyte-neuron metabolic coupling through GABA recycling.

Astrocyte-vascular coupling: Perivascular GAT2 may regulate GABA entry into the circulatory system.

Peripheral Functions

In peripheral tissues, GAT2 serves distinct functions [8]:

Kidney function: GAT2 in renal tubules reabsorbs GABA from the filtrate, contributing to systemic GABA homeostasis. Mice lacking GAT2 show increased urinary GABA excretion.

Liver function: GAT2 contributes to hepatic GABA uptake and metabolism, linking to the urea cycle and nitrogen metabolism.

Retinal function: GAT2 in retinal cells contributes to visual signal processing through GABAergic signaling in the retina.

Pain modulation: GAT2 in dorsal root ganglion neurons and peripheral sensory pathways modulates pain signaling.

Disease Associations

Epilepsy

GAT2 is relevant to epilepsy pathophysiology [9]:

Expression changes: Altered GAT2 expression has been reported in epileptic tissue.

Compensatory role: GAT2 may compensate for GAT1 dysfunction in epilepsy.

Therapeutic target: GAT2 inhibitors may have anti-seizure effects in combination with GAT1 inhibitors.

Pain Disorders

GAT2 plays a role in pain modulation [10]:

Peripheral sensitization: GAT2 in sensory neurons contributes to pain signaling.

Inflammatory pain: GAT2 expression changes in inflammatory pain states.

Therapeutic potential: GAT2 modulators may be useful for chronic pain treatment.

Kidney Disease

GAT2 is relevant to kidney function [11]:

Renal GABA handling: GAT2 is the primary GABA transporter in renal tubules.

Kidney disease: Altered GAT2 expression in diabetic nephropathy and renal fibrosis.

Therapeutic targeting: GAT2 modulators may benefit renal disease.

Retinal Degeneration

GAT2 has implications for retinal diseases [12]:

Retinal GABA homeostasis: Essential for normal retinal signaling.

Retinitis pigmentosa: GAT2 changes in degenerative retinal diseases.

Glaucoma: Altered GAT2 expression in glaucoma.

Neurological Disorders

GAT2 may be relevant to other neurological conditions [13]:

Anxiety disorders: Altered peripheral GABA in anxiety.

Mood disorders: GABA transporter changes in depression.

Neuroprotection: GAT2 modulation may offer neuroprotection.

Molecular Mechanisms

Regulation of Expression

GAT2 expression is regulated at multiple levels [14]:

Transcriptional regulation: Promoter elements respond to:

Neuronal activity
Hormonal signaling
Inflammatory cytokines
Metabolic conditions

Post-translational regulation:

Phosphorylation by PKC, PKA
Glycosylation affecting trafficking
Ubiquitination and degradation

Activity-dependent regulation: Neuronal activity can modulate GAT2 expression.

Protein Interactions

GAT2 interacts with:

Syntaxin 1A: Trafficking
Dynamin: Endocytosis
Cytoskeletal proteins: Localization

Trafficking

GAT2 trafficking involves:

ER → Golgi → plasma membrane

Endocytic recycling

Lysosomal degradation

Therapeutic Targeting

Current Approaches

Drug Development

Peripheral selectivity: Developing GAT2-selective compounds for peripheral indications.

Combination therapy: GAT1 + GAT2 inhibition for enhanced anti-seizure effects.

Targeted delivery: Direct CNS delivery to avoid peripheral effects.

Animal Models

Knockout Models

GAT2 knockout mice show [15]:

Increased urinary GABA: Elevated GABA excretion
Renal abnormalities: Changes in kidney function
Retinal changes: Altered retinal electrophysiology
Behavior changes: Some anxiety-related behaviors

Transgenic Models

Transgenic and conditional knockout models are used to study cell-type-specific functions.

Cross-Linking Connections

[SLC6A1](/genes/slc6a1) - GAT1, neuronal GABA transporter
[SLC6A11](/genes/slc6a11) - GAT3, astrocytic GABA transporter
[SLC6A12](/genes/slc6a12) - GAT4, neuropile GABA transporter
[GABRA1](/genes/gabra1) - GABA-A receptor alpha1

[GABA Signaling in Neurodegeneration](/mechanisms/gaba-imbalance)
[Astrocyte-Neuron Coupling](/mechanisms/astrocyte-neuron-coupling)
[Tonic Inhibition](/mechanisms/tonic-inhibition)

[Epilepsy](/diseases/epilepsy)
[Chronic Pain](/diseases/chronic-pain)
[Kidney Disease](/diseases/kidney-disease)
[Retinitis Pigmentosa](/diseases/retinitis-pigmentosa)

Brain Regions

[Cortex](/brain-regions/cortex)
[Hippocampus](/brain-regions/hippocampus)
[Retina](/brain-regions/retina)

Key Publications

[Madsen KK, et al. (2011). GABA transport and the pharmacology of GABA transport inhibitors. Neuropharmacology.](https://pubmed.ncbi.nlm.nih.gov/21439295/)

[Bjerke M, et al. (2011). GABA transporter 2: astrocytic and peripheral expression. Neurochem Int.](https://pubmed.ncbi.nlm.nih.gov/21316382/)

[Ju J, et al. (2016). GABA transporters in pain modulation. Curr Neuropharmacol.](https://pubmed.ncbi.nlm.nih.gov/27179567/)

[Richardson CE, et al. (2017). GABA transporters in peripheral tissues. Am J Physiol.](https://pubmed.ncbi.nlm.nih.gov/28093498/)

[McGorman J, et al. (2019). GAT2 in retinal function and disease. Prog Retin Eye Res.](https://pubmed.ncbi.nlm.nih.gov/31075298/)

Background

The study of GAT2 has revealed important insights into GABA transporter diversity and peripheral GABA homeostasis. Unlike the neuron-specific GAT1, GAT2's expression in both CNS and peripheral tissues suggests specialized functions.

Early research characterized the pharmacological properties of GABA transporters, revealing selective inhibitors for each subtype. The development of GAT2-selective tools enabled detailed functional studies.

Subsequent work established GAT2's role in peripheral organs, particularly kidney function. The recognition that peripheral GABA transport is important for systemic homeostasis expanded understanding of GABA biology.

More recent investigations have explored GAT2 as a therapeutic target for pain, kidney disease, and retinal disorders. The development of peripheral-selective GABA transporter modulators offers potential for targeted therapies.

Pathway & Interaction Diagram

Interactive diagram showing SLC6A13's key relationships in the SciDEX knowledge graph (6 connections shown).

Mermaid diagram (expand to render)

External Links

[NCBI Gene: SLC6A13](https://www.ncbi.nlm.nih.gov/gene/6404)
[UniProt: SLC6A13 (Q9NPD8)](https://www.uniprot.org/uniprot/Q9NPD8)
[Ensembl: ENSG00000110851](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110851)
[GeneCards: SLC6A13](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC6A13)

References

[Broer S, Broer A, Amino acid homeostasis and signalling (2017)](https://pubmed.ncbi.nlm.nih.gov/28437836/)

[Kandasamy P, et al, SLC transporters as therapeutic targets (2020)](https://pubmed.ncbi.nlm.nih.gov/32295719/)

[Hediger MA, et al, The ABCs of solute carriers (2004)](https://pubmed.ncbi.nlm.nih.gov/14624363/)

[Goncalves P, et al, Glucose transporters in BBB (2013)](https://pubmed.ncbi.nlm.nih.gov/23945237/)

[Verrey F, et al, Heteromeric amino acid transporter (2005)](https://pubmed.ncbi.nlm.nih.gov/15917204/)

[Palacin M, et al, Structure and function of SLC15A4 (2014)](https://pubmed.ncbi.nlm.nih.gov/24815918/)

[Amara SG, et al, Glutamate transporters (2002)](https://pubmed.ncbi.nlm.nih.gov/12176023/)

[Madsen KK, et al, GABA transport inhibitors (2011)](https://pubmed.ncbi.nlm.nih.gov/21439295/)

[Bjerke M, et al, GAT2 astrocytic and peripheral expression (2011)](https://pubmed.ncbi.nlm.nih.gov/21316382/)

[Ju J, et al, GABA transporters in pain modulation (2016)](https://pubmed.ncbi.nlm.nih.gov/27179567/)

[Richardson CE, et al, GABA transporters in peripheral tissues (2017)](https://pubmed.ncbi.nlm.nih.gov/28093498/)

[Kanner BB, et al, GABA transporter subtypes in kidney (2014)](https://pubmed.ncbi.nlm.nih.gov/24655222/)

[McGorman J, et al, GAT2 in retinal function (2019)](https://pubmed.ncbi.nlm.nih.gov/31075298/)

[Scaletta M, et al, GAT2 and visual processing (2020)](https://pubmed.ncbi.nlm.nih.gov/33094278/)

[Accardi MV, et al, Targeting GABA transporters (2022)](https://pubmed.ncbi.nlm.nih.gov/35193412/)

[Eulenburg V, et al, GABA transporters anti-epileptic (2005)](https://pubmed.ncbi.nlm.nih.gov/15664656/)

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SLC6A13 Gene

SLC6A13 Gene

SLC6A13 Gene

Introduction

Gene Overview

Protein Structure and Function

Structural Organization

Transport Mechanism

Substrate Specificity

Expression Pattern

Central Nervous System

Peripheral Tissues

Physiological Functions

CNS Functions

Peripheral Functions

Disease Associations

Epilepsy

Pain Disorders

Kidney Disease

Retinal Degeneration

Neurological Disorders

Molecular Mechanisms

Regulation of Expression

Protein Interactions

Trafficking

Therapeutic Targeting

Current Approaches

Drug Development

Animal Models

Knockout Models

Transgenic Models

Cross-Linking Connections

Related Genes and Proteins

Related Mechanisms

Related Diseases

Brain Regions

Key Publications

Background

Pathway & Interaction Diagram

External Links

See Also

References