slc39a5

slc39a5

<div class="infobox infobox-gene">
<h3>SLC39A5 (ZIP5)</h3>
<table>
<tr><th>Gene Symbol</th><td>SLC39A5</td></tr>
<tr><th>Alternative Names</th><td>ZIP5, Zrt- and Irt-like protein 5</td></tr>
<tr><th>Full Name</th><td>Solute Carrier Family 39 Member 5</td></tr>
<tr><th>Chromosomal Location</th><td>12p13</td></tr>
<tr><th>NCBI Gene ID</th><td>[283420](https://www.ncbi.nlm.nih.gov/gene/283420)</td></tr>
<tr><th>OMIM</th><td>607341</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000139514](https://www.ensembl.org/Homo_sapiens/Gene?g=ENSG00000139514)</td></tr>
<tr><th>UniProt</th><td>[Q8N4U2](https://www.uniprot.org/uniprot/Q8N4U2)</td></tr>
<tr><th>Protein Class</th><td>Zinc transporter (ZIP family, LIV-1 subfamily)</td></tr>
<tr><th>Expression</th><td>Pancreas, embryonic tissues, brain (development), testis</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

SLC39A5 (also known as ZIP5) is a member of the ZIP (Zrt-, Irt-like Protein) family of zinc transporters[@liuzzi2004]. ZIP transporters facilitate cellular zinc uptake from the extracellular environment or from intracellular compartments, playing essential roles in maintaining zinc homeostasis. Zinc is an indispensable trace element required for numerous biological processes, including enzyme catalysis, protein structure stabilization, transcriptional regulation, immune function, and synaptic signaling in the brain.

slc39a5

<div class="infobox infobox-gene">
<h3>SLC39A5 (ZIP5)</h3>
<table>
<tr><th>Gene Symbol</th><td>SLC39A5</td></tr>
<tr><th>Alternative Names</th><td>ZIP5, Zrt- and Irt-like protein 5</td></tr>
<tr><th>Full Name</th><td>Solute Carrier Family 39 Member 5</td></tr>
<tr><th>Chromosomal Location</th><td>12p13</td></tr>
<tr><th>NCBI Gene ID</th><td>[283420](https://www.ncbi.nlm.nih.gov/gene/283420)</td></tr>
<tr><th>OMIM</th><td>607341</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000139514](https://www.ensembl.org/Homo_sapiens/Gene?g=ENSG00000139514)</td></tr>
<tr><th>UniProt</th><td>[Q8N4U2](https://www.uniprot.org/uniprot/Q8N4U2)</td></tr>
<tr><th>Protein Class</th><td>Zinc transporter (ZIP family, LIV-1 subfamily)</td></tr>
<tr><th>Expression</th><td>Pancreas, embryonic tissues, brain (development), testis</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

SLC39A5 (also known as ZIP5) is a member of the ZIP (Zrt-, Irt-like Protein) family of zinc transporters[@liuzzi2004]. ZIP transporters facilitate cellular zinc uptake from the extracellular environment or from intracellular compartments, playing essential roles in maintaining zinc homeostasis. Zinc is an indispensable trace element required for numerous biological processes, including enzyme catalysis, protein structure stabilization, transcriptional regulation, immune function, and synaptic signaling in the brain.

The ZIP family consists of 14 members in humans, divided into four subfamilies based on phylogenetic analysis. ZIP5 belongs to the LIV-1 subfamily and is characterized by specific expression patterns during development and in adult tissues. Unlike some other ZIP transporters with broad expression, ZIP5 shows more restricted tissue distribution, with highest expression in the pancreas and during embryonic development.

Zinc dysregulation is implicated in various neurodegenerative diseases, including [Alzheimer's disease](/diseases/alzheimers-disease) and [Parkinson's disease](/diseases/parkinsons-disease)[@dChart2011]. Understanding the function of zinc transporters like ZIP5 provides important insights into zinc homeostasis mechanisms and their potential contributions to neurodegeneration.

Gene Structure and Protein Biology

Gene Organization

The SLC39A5 gene is located on chromosome 12p13 and consists of 12 exons encoding a 540-amino acid protein with a predicted molecular weight of approximately 58 kDa. The gene spans approximately 20 kb and exhibits typical transporter gene structure.

Protein Structure

ZIP5 shares the common topological features of ZIP family members[@pin2014]:

Transmembrane Domains:

• 8 transmembrane helices (TM1-TM8)
• N-terminal and C-terminal regions oriented toward the cytoplasm
• Long extracellular loop between TM3 and TM4
• Histidine-rich sequence in the extracellular domain (potential metal-binding site)

• HExxH motif in TM4 (helicase-like zinc-binding domain)
• Variable N-terminal region
• Proline-rich regions in some family members

Transport Mechanism

ZIP transporters function as electroneutral symporters, typically transporting zinc ions together with bicarbonate ions or in exchange for other cations. Unlike the ZnT (SLC30) family that mediates zinc efflux, ZIP transporters mediate zinc uptake into the cytoplasm.

Normal Biological Functions

Cellular Zinc Homeostasis

ZIP5 contributes to cellular zinc homeostasis as part of the coordinated network of zinc transporters[@kim2008]:

Zinc Uptake:

• Imports zinc from extracellular space
• Can also transport zinc from intracellular stores
• Functions in coordination with ZnT exporters

• Pancreas: Zinc uptake for insulin storage
• Development: Zinc supply for rapidly dividing cells
• Brain: Contribution to neuronal zinc homeostasis

Role in Development

ZIP5 plays critical roles during embryonic development[@matsuura2009][@kim2014]:

Expression Pattern:

• High expression during early embryonic stages
• Localized to developing organs (pancreas, brain, limbs)
• Dynamic expression pattern through development

• Zinc is essential for cell proliferation
• Required for proper organ formation
• Supports embryonic growth and viability

Pancreatic Function

ZIP5 is highly expressed in the pancreas[@hu2016]:

Islet Cell Function:

• ZIP5 expression in pancreatic β-cells
• May contribute to zinc uptake for insulin crystallization
• Zinc is co-secreted with insulin

• Expression in acinar cells
• Potential role in digestive enzyme production

Brain Expression and Function

Developmental Expression

ZIP5 is expressed in the developing brain[@taniguchi2010][@funahashi2014]:

Temporal Pattern:

• Highest expression during embryonic and early postnatal development
• Declines in most brain regions in adulthood
• Some persistent expression in specific regions

• Cerebral cortex (developing)
• Cerebellum (duringPurkinje cell development)
• Hippocampus (embryonic)
• Spinal cord

Role in Neuronal Development

Zinc is crucial for proper neuronal development, and ZIP5 contributes to this process:

Neuronal Proliferation:

• Zinc availability affects cell cycle progression
• Required for DNA synthesis and cell division

• Zinc-dependent transcription factors
• Signal transduction pathways

• Proper zinc levels needed for neuronal migration
• ZIP5 contributes to intracellular zinc levels

Synaptic Function

In mature neurons, zinc participates in synaptic transmission[@takeda2014][@Sekler2010]:

Synaptic Zinc:

• Stored in synaptic vesicles
• Released during neuronal activity
• Modulates NMDA and AMPA receptors

• May contribute to neuronal zinc pool
• Supports synaptic zinc dynamics

Zinc in Neurodegeneration

Alzheimer's Disease

Zinc dysregulation is a well-established feature of AD pathogenesis[@adlard2010][@dChart2011]:

Amyloid Metabolism:

• Zinc binds to amyloid-β peptides with high affinity
• Influences Aβ aggregation kinetics
• Affects amyloid plaque formation and composition

• Zinc affects tau phosphorylation through multiple mechanisms
• Modulates kinase and phosphatase activities

• Zinc homeostasis critical for synaptic plasticity
• Dysregulation contributes to learning and memory deficits

• Zinc is a cofactor for antioxidant enzymes
• Dysregulation compromises cellular defense

Parkinson's Disease

Zinc homeostasis is also relevant to PD pathogenesis:

Protein Aggregation[@dChart2011]:

• Zinc influences α-synuclein aggregation
• Affects oligomer formation and toxicity

• Zinc required for mitochondrial enzymes
• Contributes to energy metabolism

• Zinc modulates microglial activation
• Alters inflammatory responses

Other Neurodegenerative Conditions

Zinc dysregulation is observed in:

• Amyotrophic lateral sclerosis (ALS)
• Huntington's disease
• Multiple sclerosis
• Frontotemporal dementia

Expression Pattern

Tissue Distribution

ZIP5 shows distinctive expression patterns:

High Expression:

• Pancreas (both endocrine and exocrine)
• Embryonic tissues
• Developing organs

• Testis
• Small intestine
• Kidney

• Brain (higher during development)
• Liver
• Lung

Brain Region Specificity

In the developing brain, ZIP5 is expressed in:

• Cerebral cortical plate
• Cerebellar Purkinje cell layer
• Hippocampal formation
• Spinal cord ventral horn

Cellular Localization

ZIP5 localizes primarily to:

• Plasma membrane
• Intracellular vesicles
• Golgi apparatus (in some cell types)

Interaction Network

Protein Interactions

ZIP5 likely interacts with:

Transport Partners:

• Other ZIP transporters (ZIP10, ZIP8)
• ZnT transporters (for coordinated homeostasis)
• Carbonic anhydrases (for bicarbonate symport)

• Metallothioneins (zinc buffering)
• Zinc finger transcription factors
• Protein kinases (post-translational regulation)

Signaling Pathways

ZIP5 function intersects with:

• MTOR signaling (zinc-sensitive)
• MAPK pathways
• PI3K/Akt pathway
• p53-mediated apoptosis

Genetic Variants and Disease Associations

Known Variants

While SLC39A5 is not a major AD or PD risk gene like some other zinc transporters, natural variation exists:

• Multiple missense variants cataloged
• Some variants may affect transport function
• Population frequency data available

Therapeutic Implications

Targeting ZIP5 or zinc homeostasis more broadly:

• Potential for combination therapies
• Requires careful balancing of zinc levels
• Tissue-specific delivery challenges

Animal Models

Knockout Studies

Zip5 knockout mice show:

• Growth retardation
• Developmental abnormalities
• Impaired pancreas function

Limitations

• Species-specific expression patterns
• Developmental compensation
• Need for brain-specific models

Research Methods

Genetic Studies

• Expression analysis (qPCR, RNA-seq)
• Variant screening
• eQTL analysis

Molecular Biology

• Western blotting
• Immunohistochemistry
• Confocal microscopy

Functional Studies

• Zinc uptake assays
• Intracellular zinc measurements
• Transport kinetics

Model Systems

• Cell lines (HEK293, neurons)
• Mouse models
• Zebrafish (for developmental studies)

Therapeutic Implications

Rationale for Targeting

Zinc homeostasis is dysregulated in neurodegeneration, making zinc transporters attractive targets:

Advantages:

• Genetic evidence supports zinc's role
• Modifiable through pharmacological intervention
• Potential for disease modification

Strategies

Small Molecule Modulators:

• ZIP transporter activators/inhibitors
• Under development for some ZIP family members

• May benefit some patients
• Requires careful monitoring
• Not universally effective

• Targeting ZIP transporter expression
• More experimental

Challenges

• Redundancy among ZIP transporters
• Tissue-specific delivery
• Balancing zinc homeostasis
• Off-target effects

Cross-Linking to Related Concepts

Related Neurodegenerative Diseases

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

Related Mechanisms

• [Zinc Transporters](/mechanisms/zinc-transporters)
• [Zinc Homeostasis](/mechanisms/zinc-homeostasis)
• [Synaptic Zinc Signaling](/mechanisms/synaptic-zinc)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [Developmental Neurobiology](/mechanisms/developmental-neurobiology)

Related Genes

• [SLC39A10 (ZIP10)](/genes/slc39a10) — Neuronal zinc transporter
• [SLC39A11 (ZIP11)](./slc39a11) — Related zinc transporter
• [SLC39A8 (ZIP8)](./slc39a8) — Manganese/zinc transporter
• [SLC30A1 (ZnT1)](./slc30a1) — Zinc efflux transporter

Future Directions

Key Research Questions

Emerging Areas

• Single-cell transcriptomics
• Structure-function studies
• In vivo zinc imaging
• Therapeutic development

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Zinc Transporters](/mechanisms/zinc-transporters)
• [Zinc Homeostasis](/mechanisms/zinc-homeostasis)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [Synaptic Signaling](/mechanisms/synaptic-signaling)
• [Developmental Neurobiology](/mechanisms/developmental-neurobiology)

External Links

• [NCBI Gene: SLC39A5 (283420)](https://www.ncbi.nlm.nih.gov/gene/283420)
• [UniProt: Q8N4U2](https://www.uniprot.org/uniprot/Q8N4U2)
• [OMIM: 607341](https://www.omim.org/entry/607341)
• [Ensembl: ENSG00000139514](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000139514)
• [HGNC: 17769](https://www.genenames.org/data/hgnc_data.php?hgnc_id=17769)

Brain Atlas Resources

• [Allen Human Brain Atlas - SLC39A5](https://human.brain-map.org/microarray/search/show?search_term=SLC39A5)
• [BrainSpan Atlas of the Developing Human Brain](https://www.brainspan.org/search?gene=SLC39A5)
• [Allen Mouse Brain Atlas](https://mouse.brain-map.org/search?query=SLC39A5)
• [Allen Cell Type Atlas](https://celltypes.brain-map.org/?#)

References