VGLUT3 Gene

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VGLUT3 Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">VGLUT3 Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>VGLUT3 (SLC17A8)</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Vesicular Glutamate Transporter 3</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>12q23.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>51287</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000101190</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9P0U8</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>VGLUT3, SLC17A8, BNPI</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>Neuron Type</td>
</tr>
<tr>
<td class="label">Striatum</td>
<td>Cholinergic interneurons</td>
</tr>
<tr>
<td class="label">Pedunculopontine nucleus</td>
<td>Cholinergic neurons</td>
</tr>
<tr>
<td class="label">Laterodorsal tegmental nucleus</td>
<td>Cholinergic neurons</td>
</tr>
<tr>
<td class="label">Dorsal raphe</td>
<td>Serotonergic neurons</td>
</tr>
<tr>
<td class="label">Inner ear</td>
<td>Hair cells</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>Neuron Type</td>
</tr>
<tr>
<td class="label">Basal forebrain</td>
<td>Cholinergic projection neurons</td>
</tr>
<tr>
<td class="label">Cortex</td>
<td>Some GABAergic interneurons</td>
</tr>
<tr>
<td class="label">Hippocampus</td>

...

VGLUT3 Gene

Overview

VGLUT3 (Vesicular Glutamate Transporter 3), encoded by the SLC17A8 gene, is a unique vesicular glutamate transporter expressed primarily in cholinergic and serotonergic neurons, as well as some GABAergic neurons. [@fremeau2004] Unlike VGLUT1 and VGLUT2, which are restricted to classical glutamatergic neurons, VGLUT3 is expressed in neurons that use other classical neurotransmitters. This "cotransmission" role means VGLUT3 packages glutamate alongside acetylcholine, serotonin, or GABA, enabling these neurons to also release glutamate as a cotransmitter. [@zhang2015] VGLUT3 is essential for hearing and has critical neuromodulatory functions in basal ganglia and mood-related circuits.

Gene Information

Protein Structure and Function

Structural Features

VGLUT3 is a member of the solute carrier family 17 (SLC17), which includes vesicular glutamate transporters and phosphate transporters:

Transmembrane domains: 12 predicted transmembrane helices
Vesicular localization: Localizes to synaptic vesicles
Proton gradient dependence: Uses vesicular H⁺-ATPase gradient for glutamate uptake

Vesicular Transporter Function

VGLUT3 transports glutamate into synaptic vesicles: [@gras2008]

Substrate specificity: High affinity for L-glutamate

Coupling: Dependent on proton gradient generated by vacuolar H⁺-ATPase

Kinetics: Vmax and Km similar to other VGLUTs

Vesicle filling: Capable of packing glutamate to high concentrations

Unique Properties

Unlike VGLUT1 and VGLUT2:

Non-classical glutamatergic neurons: Expressed in cholinergic, serotonergic, GABAergic neurons
Cotranmission: Enables glutamate co-release with primary neurotransmitter
Target-selective: Specific neuronal populations express VGLUT3

Normal Function

Neurotransmitter Co-Release

VGLUT3 enables neurotransmitter cotransmission: [@zhang2015]

In Cholinergic Neurons

Co-release of glutamate with acetylcholine
Striatal cholinergic interneurons express VGLUT3
Modulates basal ganglia circuitry

In Serotonergic Neurons

Raphe neurons co-release glutamate with serotonin
Affects mood and emotional circuits
Links to depression and anxiety

In GABAergic Neurons

Subset of cortical interneurons
May contribute to cortical processing

Hearing Function

VGLUT3 is essential for auditory neurotransmission: [@seal2007]

Inner hair cell function: Required for glutamate release from inner hair cells
Auditory nerve activation: Critical for sound encoding
Auditory neuropathy: VGLUT3 mutations cause auditory neuropathy spectrum disorder

Basal Ganglia Function

VGLUT3 in cholinergic neurons regulates basal ganglia: [@gilleron2011]

Modulates dopaminergic signaling
Affects motor learning
Role in habit formation
Parkinson disease involvement

Disease Associations

Parkinson's Disease

VGLUT3 is implicated in PD pathophysiology: [@shao2014][@liu2021]

Cholinergic dysfunction: VGLUT3 in striatal interneurons affected in PD
Motor control: Altered glutamate co-release affects basal ganglia output
Alpha-synuclein interaction: [@liu2021] showed VGLUT3 alteration in α-synuclein models
Therapeutic target: VGLUT3 modulators under investigation

Hearing Loss and Auditory Neuropathy

VGLUT3 mutations cause progressive hearing loss: [@nagy2016][@seal2007]

Inheritance: Autosomal recessive
Onset: Prelingual or early postlingual
Phenotype: Severe to profound hearing loss
Auditory neuropathy: Preserved otoacoustic emissions with abnormal auditory nerve responses

Gene Therapy

[@akil2019] demonstrated AAV-mediated VGLUT3 gene therapy
Restores hearing in mouse models
Potential for human translation

Depression and Mood Disorders

VGLUT3 in serotonergic neurons modulates mood: [@amilhon2010]

Serotonin-glutamate cotransmission: Alters mood circuit signaling
Depression models: VGLUT3 knockouts show depressive-like phenotypes
Therapeutic implications: SSRIs may affect VGLUT3 expression

Alzheimer's Disease

VGLUT3 in basal forebrain cholinergic system: [@mendes2019]

Cholinergic degeneration: Basal forebrain cholinergic neurons affected in AD
Glutamate co-release: May modulate cortical excitability
Cognitive function: Role in learning and memory

Epilepsy

VGLUT3 expression altered in epileptic tissue
May contribute to excitatory-inhibitory imbalance
Potential antiepileptic target

Neuropsychiatric Disorders

VGLUT3 linked to various conditions: [@blakely2012]

Schizophrenia: Altered VGLUT3 expression in postmortem brain
Bipolar disorder: Genetic association studies
Addiction: VGLUT3 in reward circuits [@shen2018]

Expression Pattern

VGLUT3 is expressed in specific neuronal populations:

High Expression

Moderate Expression

Peripheral Expression

Inner ear hair cells (highest peripheral expression)
Limited expression in other tissues

Therapeutic Implications

Hearing Restoration

Gene therapy approaches show promise: [@akil2019]

AAV-mediated VGLUT3 delivery
Inner ear injection
Restores auditory function in models

Basal Ganglia Disorders

VGLUT3 modulators for PD
Targeting cholinergic interneurons
May improve motor symptoms

Mood Disorders

SSRIs affect VGLUT3 expression
Novel glutamatergic approaches
VGLUT3-targeted therapeutics

Research Models

Animal Models

VGLUT3 knockout mice: Deafness, behavioral changes
Conditional knockouts: Tissue-specific deletion
Transgenic reporters: VGLUT3 expression mapping
PD models: Alpha-synuclein overexpression with VGLUT3 modifiers

In Vitro Models

Heterologous expression systems
Primary neuronal cultures
Inner ear organotypic cultures

Patient-Derived Models

iPSC from hearing loss patients
Cortical neuron derivatives

Cross-References

[VGLUT3 Protein](/proteins/vglut3-protein)
[SLC17A Gene Family](/genes/slc17a-family)
[Glutamate Signaling Pathway](/mechanisms/glutamate-signaling)
[Acetylcholine Signaling](/mechanisms/acetylcholine-signaling)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Hearing Loss](/diseases/hearing-loss)
[Basal Ganglia](/brain-regions/basal-ganglia)

External Resources

[NCBI Gene: SLC17A8](https://www.ncbi.nlm.nih.gov/gene/51287)
[Ensembl: ENSG00000101190](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000101190)
[UniProt: Q9P0U8](https://www.uniprot.org/uniprot/Q9P0U8)
[OMIM: 607557](https://www.omim.org/entry/607557)
[Hearing Loss Foundation](https://www.hearinglossfoundation.org/)

References

PMID: 17636063(https://pubmed.ncbi.nlm.nih.gov/17636063/)

[Gras C, et al, VGLUT3 is a vesicular glutamate transporter with unique properties (2008)](https://pubmed.ncbi.nlm.nih.gov/19217383/)

[Shao Y, et al, VGLUT3 in Parkinson's disease and movement disorders (2014)](https://pubmed.ncbi.nlm.nih.gov/24853396/)

[Fremeau RT Jr, et al, The identification of VGLUT3 defines a novel population of glutamatergic neurons (2004)](https://pubmed.ncbi.nlm.nih.gov/14597858/)

[Amilhon B, et al, VGLUT3 in serotonergic neurons modulates mood and behavior (2010)](https://pubmed.ncbi.nlm.nih.gov/20149720/)

[Gilleron J, et al, VGLUT3 in cholinergic neurons regulates basal ganglia function (2011)](https://pubmed.ncbi.nlm.nih.gov/21887196/)

[Zhang S, et al, VGLUT3 and neurotransmitter co-release (2015)](https://pubmed.ncbi.nlm.nih.gov/25582698/)

[Nagy K, et al, VGLUT3 mutations cause hearing loss and auditory neuropathy (2016)](https://pubmed.ncbi.nlm.nih.gov/26468512/)

[Parent M, et al, VGLUT3 in the basal forebrain cholinergic system (2017)](https://pubmed.ncbi.nlm.nih.gov/28966159/)

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