SLC2A3 Gene

SLC2A3 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SLC2A3 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SLC2A3</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Solute Carrier Family 2 Member 3 (GLUT3)</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>12p13.31</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>6503</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>138170</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000146670</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P11166</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Major Facilitator Superfamily (MFS)</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>GLUT3</td>
</tr>
<tr>
<td class="label">Km (glucose)</td>
<td>1-2 mM</td>
</tr>
<tr>
<td class="label">Vmax</td>
<td>High</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Neurons</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>GLUT3 Expression</td>
</tr>
<tr>
<td class="label">Cerebral Cortex</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>High</td>
</tr>
<tr>
<td class="label">Basal Ganglia</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Brain Stem</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Spin

SLC2A3 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SLC2A3 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SLC2A3</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Solute Carrier Family 2 Member 3 (GLUT3)</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>12p13.31</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>6503</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>138170</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000146670</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P11166</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Major Facilitator Superfamily (MFS)</td>
</tr>
<tr>
<td class="label">Parameter</td>
<td>GLUT3</td>
</tr>
<tr>
<td class="label">Km (glucose)</td>
<td>1-2 mM</td>
</tr>
<tr>
<td class="label">Vmax</td>
<td>High</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Neurons</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>GLUT3 Expression</td>
</tr>
<tr>
<td class="label">Cerebral Cortex</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>High</td>
</tr>
<tr>
<td class="label">Basal Ganglia</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Brain Stem</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Spinal Cord</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Disease</td>
</tr>
<tr>
<td class="label">GLUT3 upregulators</td>
<td>AD</td>
</tr>
<tr>
<td class="label">Metabolic therapy</td>
<td>PD</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Neurodegeneration</td>
</tr>
<tr>
<td class="label">Small molecules</td>
<td>HD</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">GLUT1</td>
<td>Complementary</td>
</tr>
<tr>
<td class="label">GLUT4</td>
<td>Metabolic link</td>
</tr>
<tr>
<td class="label">GLUT2</td>
<td>Tissue distribution</td>
</tr>
<tr>
<td class="label">Insulin signaling</td>
<td>Pathway cross-talk</td>
</tr>
<tr>
<td class="label">AMPK</td>
<td>Energy sensing</td>
</tr>
<tr>
<td class="label">Mitochondria</td>
<td>Metabolic coupling</td>
</tr>
<tr>
<td class="label">VEGF</td>
<td>Angiogenesis</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Overview

SLC2A3 (Solute Carrier Family 2 Member 3) encodes GLUT3 (Glucose Transporter 3), a high-affinity glucose transporter with the highest uptake capacity among GLUT family members. While GLUT1 (SLC2A1) mediates basal glucose uptake across the blood-brain barrier, GLUT3 provides the high-affinity uptake system essential for neuronal glucose acquisition[@zhao2018]. The Km for glucose of GLUT3 (~1-2 mM) is substantially lower than plasma glucose concentrations (~5 mM), ensuring efficient glucose uptake even when blood glucose is relatively low.

GLUT3 is predominantly expressed in neurons, particularly in regions with high metabolic demand including the cerebral cortex, hippocampus, and cerebellar Purkinje cells. This neuron-specific expression pattern makes GLUT3 critical for cognitive function and vulnerable in neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD), GLUT3 expression and function are altered, contributing to metabolic deficits that precede overt neurodegeneration[@chen2018]. The brain's dependence on continuous glucose supply, combined with GLUT3's role as the primary neuronal glucose uptake system, positions this transporter as both a diagnostic biomarker candidate and therapeutic target.

Gene Information

Molecular Function

Glucose Transporter Activity

GLUT3 catalyzes facilitative glucose diffusion:

Transport mechanism: Alternating access (rocker-switch model) Direction: Bidirectional, following concentration gradient Substrates: D-Glucose, D-Galactose, D-Mannose Inhibitors: Cytochalasin B, phloretin, forskolin

Kinetic Properties

GLUT3 exhibits distinctive kinetics[@kandasamy2020]:

The low Km enables efficient glucose uptake at physiological glucose concentrations, providing neurons with autonomous glucose sensing capabilities.

Structural Features

GLUT3 is a polytopic membrane protein with:

• 12 transmembrane domains: Alpha-helical segments
• Intracellular N- and C-termini: Regulatory sequences
• Exofacial substrate binding site: Glucose recognition
• -cytolasmic gate: Conformational change
• Sugar-binding pocket: Residues for substrate specificity

Brain Function

Neuronal Glucose Uptake

GLUT3 serves as the primary glucose uptake system in neurons[@zhao2018]:

Regional Expression

Cellular Distribution

• Neuronal soma: High expression
• Dendrites: Enriched in dendritic fields
• Axon terminals: Active zones
• Glia: Low (GLUT1 dominates)

Role in Neurodegenerative Diseases

Alzheimer's Disease

In AD, GLUT3 alterations contribute to metabolic deficits[@liu2024]:

1. Reduced Expression: GLUT3 protein and mRNA decreased in AD brain 2. Impaired Trafficking: Reduced dendritic localization 3. Energy Deficits: Precedes clinical symptoms 4. Correlation with Cognition: GLUT3 correlates with MMSE scores

Mechanisms linking GLUT3 to AD:

• Aβ reduces GLUT3 expression
• Tau pathology alters trafficking
• Neuroinflammation affects regulation

Parkinson's Disease

GLUT3 in PD[@kim2023]:

1. Dopaminergic neuron vulnerability: High GLUT3 in vulnerable neurons 2. Mitochondrial dysfunction: Links to metabolic stress 3. Activity changes: Altered regulation in PD brain 4. Therapeutic implications: GLUT3 modulators in development

Other Neurodegenerative Conditions

GLUT3 alterations in:

• Huntington's Disease: Reduced expression in striatum
• ALS: Motor neuron metabolism affected
• FTD: Frontal cortex involvement
• Migraine: Vascular coupling

Therapeutic Implications

Therapeutic Targets

GLUT3 represents a promising target[@dang2023]:

1. Up-regulators: Increase GLUT3 expression 2. Activity enhancers: Improve transport kinetics 3. Trafficking modulators: Improve dendritic targeting 4. Combination approaches: With metabolic therapies

Strategies in Development

Diagnostic Potential

GLUT3 as biomarker:

• CSF GLUT3: Disease progression
• PET ligands: Under development
• Genetic variants: Risk modification

Interaction Network

GLUT3 interacts with:

Genetic Variants

Disease-Relevant Variants

• Missense variants: Altered transport kinetics
• Promoter variants: Expression differences
• Regulatory variants: Tissue-specific effects

Population Genetics

• Common variants: Modest effect on disease risk
• Rare variants: Penetrant disease associations

Research Tools

Model Systems

• Knockout mice: Preinatal lethal (brain-specific deletion viable)
• Transgenic overexpression: Neuronal and general
• iPSC neurons: Patient-specific modeling
• Organoids: Cerebral organoid metabolic studies

Detection Methods

• Antibodies: GLUT3-specific detection
• Transport assays: Radiolabeled glucose uptake
• PET ligands: Under development
• Expression arrays: Transcriptomic analysis

Summary

SLC2A3 encodes GLUT3, the high-affinity neuronal glucose transporter essential for brain glucose acquisition. With a Km substantially lower than other GLUTs, GLUT3 ensures neurons obtain sufficient glucose even during metabolic stress. GLUT3 is critical for cognitive function, regional brain metabolism, and neuronal survival. In neurodegenerative diseases, GLUT3 alterations contribute to metabolic deficits that precede and drive neurodegenerative processes. The transporter's central role in neuronal metabolism, combined with its disease-associated changes, makes it a promising therapeutic target. Ongoing research aims to develop GLUT3-modulating compounds, gene therapies, and diagnostic approaches for AD, PD, and related disorders.

References