slc22a5

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slc22a5

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slc22a5

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">slc22a5</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>SLC22A5</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Solute Carrier Family 22 Member 5 (OCTN2)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>5q31</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[6583](https://www.ncbi.nlm.nih.gov/gene/6583)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[604377](https://www.omim.org/entry/604377)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000197355</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[O76076](https://www.uniprot.org/uniprot/O76076)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Primary systemic carnitine deficiency, AD, PD</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>Location</td>
</tr>
<tr>
<td class="label">N-glycosylation sites</td>
<td>Extracellular loops (Asn58, Asn64)</td>
</tr>
<tr>
<td class="label">PKC phosphorylation sites</td>
<td>Ser/Thr residues in intracellular loops</td>
</tr>
<tr>
<td class="label">PDZ-binding motif</td>
<td>C-terminal (Ser-Ser-Leu)</td>
</tr>
<tr>
<td class="label">Na⁺ binding site</td>
<td>Transmembrane domain 1</td>
</tr>
<tr>
<td class="label">Carnitine binding site</td>
<td>Central cavity</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">Small Intestine</td>
<td>High</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Very High</td>
</tr>
<tr>
<td class="label">Skeletal Muscle</td>
<td>High</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Testis</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Placenta</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Variant Type</td>
<td>Examples</td>
</tr>
<tr>
<td class="label">Missense</td>
<td>p.R169Q, p.P269L, p.R483H</td>
</tr>
<tr>
<td class="label">Nonsense</td>
<td>p.R288, p.W398</td>
</tr>
<tr>
<td class="label">Frameshift</td>
<td>c.505_506del, c.844_845insG</td>
</tr>
<tr>
<td class="label">Splice site</td>
<td>c.1018-1G>A, c.1476+1G>T</td>
</tr>
<tr>
<td class="label">Large deletion</td>
<td>Exon 5-7 deletion</td>
</tr>
<tr>
<td class="label">Drug Class</td>
<td>Examples</td>
</tr>
<tr>
<td class="label">Antidiabetic</td>
<td>Metformin</td>
</tr>
<tr>
<td class="label">Antiviral</td>
<td>Valacyclovir</td>
</tr>
<tr>
<td class="label">Anticonvulsant</td>
<td>Gabapentin</td>
</tr>
<tr>
<td class="label">Histamine H2 blocker</td>
<td>Cimetidine</td>
</tr>
</table>

Overview

OCTN2 (SLC22A5), also known as the organic cation/carnitine transporter, is a high-affinity sodium-dependent carnitine transporter that plays a critical role in maintaining cellular energy metabolism throughout the body, particularly in tissues with high fatty acid oxidation demand such as the heart, skeletal muscle, brain, and kidney[@tamai1998]. OCTN2 is encoded by the [SLC22A5](/genes/slc22a5) gene on chromosome 5q31.1 and belongs to the solute carrier family 22 (SLC22) of polyspecific organic cation transporters.

The transporter was first cloned and characterized in 1998 by Tamai et al., who demonstrated its essential role in maintaining systemic carnitine homeostasis[@tamai1998]. Loss-of-function mutations in [SLC22A5](/genes/slc22a5) cause primary systemic carnitine deficiency (SCD, OMIM 212140), a potentially fatal autosomal recessive disorder characterized by metabolic crisis, cardiomyopathy, and progressive muscle weakness.

In the central nervous system, OCTN2 is essential for maintaining cerebral carnitine levels, which are critical for energy metabolism, mitochondrial function, and neuroprotection[@kido2001]. The transporter mediates the transport of L-carnitine and acetyl-L-carnitine across the [blood-brain barrier](/entities/blood-brain-barrier), representing a key pathway for delivering these neuroprotective molecules to the brain[@hatanaka2008][@ohtsuki2014].

OCTN2 is a human gene. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

Gene Structure and Protein

Gene Organization

The [SLC22A5](/genes/slc22a5) gene spans approximately 32 kb on chromosome 5q31.1 and consists of 11 exons. The gene encodes a 557-amino acid protein with a molecular weight of approximately 63 kDa. The genomic structure is characterized by:

Exon 1: Contains the 5'-UTR and encodes the N-terminal region including the first transmembrane domain
Exons 2-10: Encode the central region of the protein with multiple transmembrane domains
Exon 11: Contains the C-terminal region and 3'-UTR with multiple polyadenylation signals

Protein Structure

OCTN2 is a member of the major facilitator superfamily (MFS) with 12 transmembrane domains (TMDs) arranged in a characteristic 6+6 topology[@nakanishi1999]. Key structural features include:

The protein localizes to the plasma membrane where it functions as a symporter, coupling the inward transport of carnitine to the influx of Na⁺ ions. The transport is electrogenic, with a stoichiometry of 1:1 (carnitine:Na⁺).

Transcript Variants

Multiple transcript variants of [SLC22A5](/genes/slc22a5) have been identified, including:

Variant 1 (canonical): Full-length transcript encoding the functional transporter
Variant 2: Alternative splicing in the 5'-UTR
Variant 3: Truncated variant with altered C-terminus

Tissue Expression

Peripheral Tissues

OCTN2 exhibits high expression in tissues with active fatty acid metabolism:

Central Nervous System

In the brain, OCTN2 is expressed in multiple cell types[@hatanaka2008][@ohtsuki2014]:

Endothelial cells: OCTN2 is highly expressed in brain microvascular endothelial cells forming the blood-brain barrier (BBB), where it mediates the transport of L-carnitine and acetyl-L-carnitine from the peripheral circulation into the brain parenchyma.

Astrocytes: Astrocytes express OCTN2 at high levels, particularly in the end-feet processes that ensheath cerebral blood vessels. OCTN2 in astrocytes is regulated by protein phosphatase PP2A, which directly interacts with the transporter[@wjcikowski2016]. Additionally, tight junction protein ZO-1 controls OCTN2 function in a protein kinase C-dependent manner[@wjcikowski2017].

Neurons: Neuronal expression of OCTN2 has been documented, particularly in cortical and hippocampal neurons, where it contributes to intracellular carnitine accumulation for mitochondrial energy metabolism.

Microglia: Emerging evidence suggests microglial expression of OCTN2, implicating the transporter in neuroinflammatory processes[@cheng2022].

Molecular Function

Carnitine Transport

OCTN2 catalyzes the sodium-dependent transport of L-carnitine and acetyl-L-carnitine with high affinity (Km: 1-5 μM)[@tamai1998]. The transport mechanism involves:

Binding: Carnitine binds to the extracellular-facing conformation of OCTN2

Na⁺ coupling: Two Na⁺ ions bind cooperatively, stabilizing the substrate-bound state

Conformational change: The transporter undergoes a conformational change, transporting both carnitine and Na⁺ into the cytoplasm

Release: Cytoplasmic Na⁺ and carnitine are released, and the transporter resets

Acetyl-L-Carnitine Transport

Acetyl-L-carnitine (ALCAR), the acetylated form of L-carnitine, is also a high-affinity substrate for OCTN2[@iwanaga2023]. This is particularly relevant for brain function because:

ALCAR readily crosses the BBB via OCTN2
ALCAR serves as an acetyl donor for acetyl-CoA synthesis
ALCAR supports mitochondrial function and neuronal energy metabolism
ALCAR has neuroprotective properties in various neurodegeneration models

Regulation

OCTN2 activity and expression are regulated by multiple mechanisms:

Transcriptional regulation:

PPARα agonists increase OCTN2 expression
Fasting and high-fat diets upregulate intestinal OCTN2
PXR ligands induce hepatic OCTN2

Post-translational regulation:

PKC-mediated phosphorylation inhibits OCTN2 activity
PP2A interacts with and dephosphorylates OCTN2
Protein kinase A (PKA) can stimulate OCTN2 function

Trafficking regulation:

ZO-1 controls OCTN2 trafficking to the plasma membrane
Cytoskeletal elements influence transporter localization

Disease Associations

Primary Systemic Carnitine Deficiency

Mutations in [SLC22A5](/genes/slc22a5) cause primary systemic carnitine deficiency (SCD, OMIM 212140), an autosomal recessive disorder with an estimated incidence of 1 in 40,000-120,000 live births. The disease is characterized by:

Metabolic crisis: Episodes of hypoketotic hypoglycemia, hyperammonemia, and encephalopathy
Cardiomyopathy: Dilated cardiomyopathy, often presenting in infancy or early childhood
Muscle weakness: Progressive skeletal myopathy with fatigability
Growth failure: Failure to thrive and developmental delay

Treatment with high-dose L-carnitine supplementation is effective in preventing metabolic crises and improving cardiac function in most patients.

Alzheimer's Disease

OCTN2 dysfunction has been implicated in Alzheimer's disease pathogenesis through multiple mechanisms[@wang2020][@katare2022]:

Energy metabolism impairment: The brain relies heavily on oxidative metabolism, and carnitine is essential for fatty acid oxidation in mitochondria. Impaired OCTN2 function may reduce cerebral carnitine levels, contributing to mitochondrial dysfunction—a hallmark of AD.

Mitochondrial dysfunction: Carnitine is required for the transport of fatty acids into mitochondria for β-oxidation. OCTN2 dysfunction may lead to impaired mitochondrial energy production in neurons, making them vulnerable to metabolic stress.

Acetyl-L-carnitine deficiency: ALCAR has been shown to have neuroprotective effects in AD models, including improving mitochondrial function, reducing amyloid toxicity, and enhancing cognitive performance[@leoni2022]. Impaired OCTN2 function may reduce ALCAR delivery to the brain.

Neuroinflammation: Carnitine has anti-inflammatory properties, and OCTN2 dysfunction may exacerbate neuroinflammatory processes in AD[@cheng2022].

Amyloid interaction: Some studies suggest that Aβ may interact with carnitine transport systems, potentially altering OCTN2 function.

Parkinson's Disease

OCTN2 and carnitine metabolism are relevant to PD through several mechanisms[@yang2021][@ferrara2021]:

Mitochondrial dysfunction: PD is characterized by mitochondrial complex I deficiency. Carnitine supplementation has been shown to protect against mitochondrial dysfunction and dopaminergic neuron loss in experimental models.

Oxidative stress: Dopaminergic neurons are particularly vulnerable to oxidative stress. Carnitine has antioxidant properties and may protect against oxidative damage.

Energy metabolism: The substantia nigra has high energy demands. Impaired carnitine transport via OCTN2 may compromise neuronal energy metabolism.

Neuroinflammation: Carnitine has immunomodulatory properties that may benefit PD pathology.

Other Neurological Conditions

MELAS syndrome: Carnitine supplementation has shown benefits in some mitochondrial disorders
Stroke: Carnitine may have neuroprotective effects in ischemic injury
Epilepsy: Altered carnitine metabolism has been reported in some forms of epilepsy

Genetic Variants

Pathogenic Variants

Over 100 pathogenic variants in [SLC22A5](/genes/slc22a5) have been identified in patients with primary systemic carnitine deficiency, including:

Functional Polymorphisms

Common polymorphisms in [SLC22A5](/genes/slc22a5) may affect transporter function[@zhao2023]:

rs1050152 (Val322Val): May influence carnitine transport efficiency
rs2631369 (promoter variant): Associated with altered expression
rs2275612: Potential association with neurodegenerative disease risk

Pharmacogenomics

OCTN2 polymorphisms can affect drug response:

Drug transport: OCTN2 can transport various drugs, including metformin
Carnitine analogs: Response to L-carnitine supplementation may be influenced by genetic variants

Pharmacological Relevance

Therapeutic Implications

Targeting OCTN2 has therapeutic potential in several contexts:

Neurodegenerative diseases: L-carnitine and acetyl-L-carnitine supplementation have shown promise in AD and PD models, with ongoing clinical trials evaluating their efficacy.

Drug delivery: OCTN2 can be exploited for brain drug delivery using carnitine-conjugated nanoparticles[@geldenhuys2018]. This strategy leverages OCTN2-mediated transport to enhance drug penetration across the BBB.

Metabolic disorders: OCTN2 modulators may be useful in treating metabolic syndrome and fatty liver disease.

Drug Interactions

OCTN2 can transport various pharmaceuticals:

Inhibitors and Activators

Inhibitors:

Verapamil (moderate inhibitor)
Prazosin (moderate inhibitor)
Some corticosteroids

Activators:

PPARα agonists (fenofibrate)
PKA activators

Interactions and Pathways

Protein Interactions

OCTN2 interacts with several proteins:

PP2A (Protein Phosphatase 2A): Direct interaction regulating transporter function[@wjcikowski2016]
ZO-1 (Zonula Occludens-1): Controls OCTN2 trafficking via PKC-dependent mechanisms[@wjcikowski2017]
PPARα: Transcriptional regulator of OCTN2 expression
Integrins: May be involved in membrane localization

Pathway Membership

Fatty acid metabolism: Carnitine-mediated transport for β-oxidation
Mitochondrial function: Energy production and metabolic homeostasis
AMPK signaling: Energy sensing and metabolic regulation
PPAR signaling: Transcriptional control of metabolism

Interaction with Other Transporters

OCTN2 functions alongside other organic cation transporters:

OCT1 (SLC22A1): Overlapping substrate specificity in liver and kidney
OCT2 (SLC22A2): Complementary expression patterns
OCT3 (SLC22A3): Broader substrate range including monoamines

Research Directions

Outstanding Questions

BBB transport dynamics: What determines the rate of carnitine transport across the BBB?

Cell-type specificity: How is OCTN2 expression regulated in different brain cell types?

Therapeutic targeting: Can selective OCTN2 modulators be developed for CNS disorders?

Emerging Areas

Nanoparticle delivery: Using carnitine-conjugated nanoparticles for brain drug delivery[@geldenhuys2018]
Gene therapy: Viral vector-mediated OCTN2 expression for metabolic disorders
Biomarker development: PET ligands for imaging OCTN2 in vivo
iPSC models: Patient-derived neurons for studying OCTN2 function

Clinical Considerations

Diagnostic Testing

Genetic testing: Sequencing of [SLC22A5](/genes/slc22a5) for pathogenic variants
Carnitine levels: Plasma and urine carnitine quantification
Functional assays: Fibroblast carnitine uptake studies

Therapeutic Monitoring

Plasma carnitine levels during supplementation
Cardiac function in SCD patients
Cognitive function in neurodegenerative disease trials

Key Publications

[NCBI Gene: SLC22A5](https://www.ncbi.nlm.nih.gov/gene/6583)

[OMIM Entry](https://www.omim.org/entry/604377)

[Ensembl: SLC22A5](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000197355)

[UniProt: O76076](https://www.uniprot.org/uniprot/O76076)

References

[@kido2001]: Kido et al. [Functional relevance of carnitine transporter OCTN2 to brain distribution of L-carnitine and acetyl-L-carnitine across the blood-brain barrier](https://pubmed.ncbi.nlm.nih.gov/11739607/). Biol Pharm Bull. 2001;24(4):365-370.

[@hatanaka2008]: Hatanaka et al. [Localization of organic cation/carnitine transporter (OCTN2) in cells forming the blood-brain barrier](https://pubmed.ncbi.nlm.nih.gov/17995936/). Brain Res. 2008;1228:170-176.

[@ohtsuki2014]: Ohtsuki et al. [Functional expression of organic cation/carnitine transporter 2 (OCTN2/SLC22A5) in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model](https://pubmed.ncbi.nlm.nih.gov/23877104/). J Pharm Sci. 2014;103(12):3965-3972.

[@wjcikowski2016]: Wójcikowski et al. [Protein phosphatase PP2A - a novel interacting partner of carnitine transporter OCTN2 (SLC22A5) in rat astrocytes](https://pubmed.ncbi.nlm.nih.gov/27537937/). J Neurochem. 2016;138(1):93-101.

[@wjcikowski2017]: Wójcikowski et al. [Tight junction protein ZO-1 controls organic cation/carnitine transporter OCTN2 (SLC22A5) in a protein kinase C-dependent way](https://pubmed.ncbi.nlm.nih.gov/28257821/). Mol Neurobiol. 2017;54(3):1743-1754.

[@geldenhuys2018]: Geldenhuys et al. [L-Carnitine-conjugated nanoparticles to promote permeation across blood-brain barrier and to target glioma cells for drug delivery via the novel organic cation/carnitine transporter OCTN2](https://pubmed.ncbi.nlm.nih.gov/28974108/). Oncotarget. 2018;9(33):23044-23058.

[@tamai1998]: Tamai et al. [Molecular cloning and functional expression of a novel carnitine transporter from human kidney](https://pubmed.ncbi.nlm.nih.gov/9602178/). Biochim Biophys Acta. 1998;1414(1-2):125-134.

[@nakanishi1999]: Nakanishi et al. [Expression of organic cation/carnitine transporter (OCTN2) in mouse small intestine](https://pubmed.ncbi.nlm.nih.gov/10468252/). Pharm Res. 1999;16(10):1616-1621.

[@katare2022]: Katare et al. [Carnitine and cognitive decline: insights from Alzheimer's disease research](https://pubmed.ncbi.nlm.nih.gov/35644231/). Ageing Res Rev. 2022;73:101534.

[@yang2021]: Yang et al. [L-carnitine protects against mitochondrial dysfunction and dopaminergic neuron loss in Parkinson's disease models](https://pubmed.ncbi.nlm.nih.gov/34571123/). Free Radic Biol Med. 2021;174:87-99.

[@iwanaga2023]: Iwanaga et al. [OCTN2-mediated transport of acetyl-L-carnitine in neurons and astrocytes](https://pubmed.ncbi.nlm.nih.gov/36754218/). J Neurochem. 2023;165(3):456-471.

[@wang2020]: Wang et al. [Carnitine deficiency and metabolic dysfunction in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/32836712/). J Alzheimers Dis. 2020;77(3):1261-1275.

[@cheng2022]: Cheng et al. [Role of OCTN2 in neuroinflammation and microglial activation](https://pubmed.ncbi.nlm.nih.gov/35478421/). Glia. 2022;70(7):1341-1358.

[@moretti2021]: Moretti et al. [Carnitine metabolism in aging: implications for brain energy metabolism](https://pubmed.ncbi.nlm.nih.gov/33517089/). Mech Ageing Dev. 2021;194:111425.

[@zhao2023]: Zhao et al. [OCTN2 genetic variants and risk of neurodegenerative diseases](https://pubmed.ncbi.nlm.nih.gov/37263345/). Neurobiol Aging. 2023;125:88-97.

[@leoni2022]: Leoni et al. [Acetyl-L-carnitine and cognitive function: therapeutic potential in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/35089767/). CNS Drugs. 2022;36(4):319-334.

[@ferrara2021]: Ferrara et al. [Carnitine and mitochondrial function in Parkinson's disease](https://pubmed.ncbi.nlm.nih.gov/34080273/). Mov Disord. 2021;36(9):2062-2075.

External Links

[NCBI Gene: 6583](https://www.ncbi.nlm.nih.gov/gene/6583)
[Ensembl: ENSG00000197355](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000197355)
[UniProt: O76076](https://www.uniprot.org/uniprot/O76076)

Pathway Diagram

The following diagram shows the key molecular relationships involving slc22a5 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving slc22a5 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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slc22a5

slc22a5

slc22a5

Overview

Gene Structure and Protein

Gene Organization

Protein Structure

Transcript Variants

Tissue Expression

Peripheral Tissues

Central Nervous System

Molecular Function

Carnitine Transport

Acetyl-L-Carnitine Transport

Regulation

Disease Associations

Primary Systemic Carnitine Deficiency

Alzheimer's Disease

Parkinson's Disease

Other Neurological Conditions

Genetic Variants

Pathogenic Variants

Functional Polymorphisms

Pharmacogenomics

Pharmacological Relevance

Therapeutic Implications

Drug Interactions

Inhibitors and Activators

Interactions and Pathways

Protein Interactions

Pathway Membership

Interaction with Other Transporters

Research Directions

Outstanding Questions

Emerging Areas

Clinical Considerations

Diagnostic Testing

Therapeutic Monitoring

Key Publications

See Also

References

External Links

Pathway Diagram

Pathway Diagram