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>
<td>Specific interneuron populations [@toth2019]</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
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.
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 concentrationsUnique 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/)