slc22a2

slc22a2

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">slc22a2</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>SLC22A2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Solute Carrier Family 22 Member 2 (OCT2)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>6q26</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[6580](https://www.ncbi.nlm.nih.gov/gene/6580)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[603731](https://www.omim.org/entry/603731)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000112406</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[O15228](https://www.uniprot.org/uniprot/O15228)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>AD, PD, depression, drug response variability</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>Location</td>
</tr>
<tr>
<td class="label">N-glycosylation</td>
<td>Extracellular loops</td>
</tr>
<tr>
<td class="label">PKC sites</td>
<td>Intracellular loops</td>
</tr>
<tr>
<td class="label">PDZ motif</td>
<td>C-terminal</td>
</tr>
<tr>
<td class="label">Substrate binding</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">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Inte

slc22a2

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">slc22a2</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>SLC22A2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Solute Carrier Family 22 Member 2 (OCT2)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>6q26</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[6580](https://www.ncbi.nlm.nih.gov/gene/6580)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[603731](https://www.omim.org/entry/603731)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000112406</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[O15228](https://www.uniprot.org/uniprot/O15228)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>AD, PD, depression, drug response variability</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>Location</td>
</tr>
<tr>
<td class="label">N-glycosylation</td>
<td>Extracellular loops</td>
</tr>
<tr>
<td class="label">PKC sites</td>
<td>Intracellular loops</td>
</tr>
<tr>
<td class="label">PDZ motif</td>
<td>C-terminal</td>
</tr>
<tr>
<td class="label">Substrate binding</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">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Intestine</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Low</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>Acyclovir, ganciclovir</td>
</tr>
<tr>
<td class="label">Antidepressant</td>
<td>Imipramine, amitriptyline</td>
</tr>
<tr>
<td class="label">Neuroleptic</td>
<td>Chlorpromazine</td>
</tr>
<tr>
<td class="label">Chemotherapeutic</td>
<td>Cisplatin</td>
</tr>
<tr>
<td class="label">SNP</td>
<td>Function</td>
</tr>
<tr>
<td class="label">rs2019195</td>
<td>Coding (Ala44Ser)</td>
</tr>
<tr>
<td class="label">rs3126913</td>
<td>Promoter</td>
</tr>
<tr>
<td class="label">rs316008</td>
<td>3'UTR</td>
</tr>
<tr>
<td class="label">rs4420638</td>
<td>Regulatory</td>
</tr>
<tr>
<td class="label">Interaction Type</td>
<td>Drugs</td>
</tr>
<tr>
<td class="label">Inhibitors</td>
<td>Cimetidine, quinidine</td>
</tr>
<tr>
<td class="label">Substrates</td>
<td>Metformin, cisplatin</td>
</tr>
<tr>
<td class="label">Inducers</td>
<td>Rifampin</td>
</tr>
</table>

{{.infobox .infobox-gene}}

Overview

Organic cation transporter 2 (OCT2), encoded by the [SLC22A2](/genes/slc22a2) gene on chromosome 6q26, is a polyspecific transmembrane transporter that mediates the Na⁺-independent transport of organic cations across cell membranes. OCT2 belongs to the solute carrier family 22 (SLC22) and plays crucial roles in neurotransmitter clearance, drug disposition, and cellular homeostasis in both the peripheral organs and the central nervous system[@grundemann1998].

First cloned in 1998, OCT2 was the first mammalian organic cation transporter to be characterized at the molecular level[@grundemann1998]. The transporter is expressed at high levels in the kidney, where it plays a major role in the renal secretion of organic cations, and in the brain, where it participates in the clearance of neurotransmitters from the extracellular space.

In the brain, OCT2 is strategically positioned to regulate monoaminergic neurotransmission. It is expressed in monoaminergic and cholinergic axon terminals[@araya2016], where it contributes to the clearance of dopamine, norepinephrine, and other neuroactive cations from the extracellular space. This function complements the high-affinity reuptake transporters (DAT, NET, SERT) by providing a lower-affinity, higher-capacity clearance mechanism for neurotransmitters that escape synaptic recapture.

OCT2 is a human gene. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration and neuropsychiatric disorders.

Gene Structure and Protein

Gene Organization

The [SLC22A2](/genes/slc22a2) gene spans approximately 31 kb on chromosome 6q26 and consists of 11 exons. The gene encodes a 556-amino acid protein with a molecular weight of approximately 63 kDa. Key features include:

• Alternative splicing: Multiple transcript variants have been identified in human brain[@cokus2010], including variants with altered 5'-UTR and C-terminal regions
• Promoter region: Contains response elements for various transcription factors including PXR, CAR, and HNF4α
• Conservation: High evolutionary conservation across mammals

Protein Structure

OCT2 is a member of the major facilitator superfamily (MFS) with 12 transmembrane domains (TMDs)[@koepsell2013]. Key structural features include:

The transporter operates as an electrophoretic uniporter, facilitating the diffusion of organic cations across the plasma membrane in response to the electrochemical gradient.

Transport Kinetics

OCT2 exhibits the following transport characteristics:

• Km for dopamine: 100-300 μM (low-affinity, high-capacity)
• Km for MPP⁺: 10-50 μM
• Stoichiometry: Electrogenic, 1:1 exchange or facilitated diffusion

Tissue Expression

Peripheral Expression

In the kidney, OCT2 is primarily localized in the basolateral membrane of proximal tubule cells, where it mediates the uptake of organic cations from the blood for subsequent secretion into the urine[@keber2021].

Central Nervous System Expression

OCT2 is widely expressed in the brain[@takeda2019]:

Monoaminergic regions:

• Substantia nigra (dopaminergic neurons)
• Locus coeruleus (noradrenergic neurons)
• Dorsal raphe (serotonergic neurons)

• CA1-CA3 pyramidal neurons
• Dentate gyrus granule cells

• Layer V pyramidal neurons
• Interneurons

Molecular Function

Neurotransmitter Transport

OCT2 transports a variety of neuroactive organic cations:

Monoamines:

• [Dopamine](/mechanisms/dopaminergic-signaling) Norepinephrine (noradrenaline)
• Serotonin (5-HT)
• Histamine

• MPP⁺ (1-methyl-4-phenylpyridinium, a neurotoxin)
• Tryptophan and metabolites
• Polyamines (putrescine, spermine, spermidine)

Drug Transport

OCT2 transports numerous drugs and xenobiotics[@eng2015]:

Signaling Regulation

Beyond neurotransmitter transport, OCT2 participates in intracellular signaling:

Dopamine D1 receptor signaling: OCT2 regulates dopamine D1 receptor signaling at the Golgi apparatus[@song2022], a novel function that affects receptor trafficking and signal transduction.

GSK3β signaling: OCT2 controls vulnerability to stress via GSK3β signaling[@wu2014]. This pathway is relevant to both mood disorders and neurodegeneration.

Disease Associations

Alzheimer's Disease

OCT2 dysfunction may contribute to AD through several mechanisms:

Neurotransmitter dysregulation: AD is associated with deficits in monoaminergic neurotransmission. OCT2-mediated clearance of extracellular monoamines may be altered in AD, contributing to neurotransmission deficits.

Glutamate toxicity: Dysregulated monoamine clearance may affect glutamatergic signaling, which is central to excitotoxicity in AD.

Stress response: OCT2 modulates stress vulnerability through GSK3β signaling[@wu2014], a pathway implicated in AD pathogenesis.

Cholinergic function: OCT2 is expressed in cholinergic neurons and may influence cholinergic signaling, which is severely compromised in AD[@kido2021].

Parkinson's Disease

OCT2 plays significant roles in PD pathophysiology[@iavine2022]:

Dopamine homeostasis: OCT2 contributes to extraneuronal dopamine clearance in the substantia nigra and striatum. Altered OCT2 function may affect dopamine metabolism and clearance.

MPTP toxicity: OCT2 transports MPP⁺, the neurotoxin that causes Parkinsonian symptoms. Genetic variants in [SLC22A2](/genes/slc22a2) may influence susceptibility to environmental neurotoxins.

L-DOPA response: OCT2 may influence the brain penetration and efficacy of L-DOPA, the primary PD treatment.

Neuroprotection: OCT2 modulators may have neuroprotective effects through modulation of cholinergic and dopaminergic signaling[@kido2021].

Depression and Anxiety

OCT2 is implicated in mood disorders:

SSRI efficacy: OCT2 contributes to SSRI antidepressant efficacy by controlling tryptophan availability in the brain[@caswell2023]. This provides a novel mechanism for antidepressant action beyond serotonin reuptake inhibition.

Stress response: OCT2 controls vulnerability to stress and GSK3β signaling[@wu2014], a pathway central to depression pathophysiology.

Tryptophan metabolism: By regulating brain tryptophan levels, OCT2 influences the synthesis of serotonin and kynurenine metabolites, affecting both mood and immune function.

Drug Response Variability

OCT2 polymorphisms significantly influence drug response[@warner2003][@melen2020]:

• Metformin: OCT2-mediated uptake affects glucose-lowering efficacy
• Cisplatin: OCT2 contributes to drug-induced nephrotoxicity
• Methamphetamine: Genetic variants influence response and vulnerability
• Antidepressants: Variable brain penetration affects treatment outcomes

Genetic Variants

Functional Polymorphisms

Several polymorphisms in [SLC22A2](/genes/slc22a2) have been characterized:

Disease-Associated Variants

• Parkinson's disease: Some variants associated with altered risk
• Depression: May influence antidepressant response
• Drug response: Multiple variants affect drug pharmacokinetics

Pharmacological Relevance

Therapeutic Targeting

Modulating OCT2 activity has therapeutic potential:

Antidepressants: Some SSRIs inhibit OCT2, contributing to their mechanism of action through effects on tryptophan and monoamine transport[@caswell2023].

Parkinson's disease: OCT2 modulators may enhance dopaminergic function or protect against neurotoxins.

Neuroprotection: OCT2 inhibitors like quinidine may have neuroprotective properties in combination with other agents[@kido2021].

Drug Interactions

Brain Penetration

OCT2 expression at the blood-brain barrier influences drug brain penetration:

• Some antidepressants cross the BBB via OCT2
• Drug-drug interactions at OCT2 can affect CNS effects
• Genetic variants may alter brain drug levels

Interactions and Pathways

Protein Interactions

• Dopamine D1 receptor: Regulation of receptor trafficking at Golgi[@song2022]
• GSK3β: Modulation of stress signaling pathways[@wu2014]
• PP2A: Possible regulatory interactions

Pathway Membership

• Monoamine metabolism: Dopamine and norepinephrine clearance
• Drug metabolism: Pharmacokinetics
• Stress response: GSK3β signaling
• Cellular cation homeostasis: Organic cation transport

Research Directions

Outstanding Questions

Emerging Areas

• Gene therapy: Viral vector-mediated OCT2 expression
• iPSC models: Patient-derived neurons for functional studies
• PET imaging: Development of OCT2-selective ligands

Clinical Considerations

Pharmacogenetic Testing

OCT2 genotyping may inform:

• Metformin dosing
• Cisplatin dosing and toxicity risk
• Antidepressant selection

Disease Monitoring

• PET ligands for in vivo OCT2 imaging
• Biomarkers for transporter function

Key Publications

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Dopamine Pathway](/mechanisms/dopamine-biosynthesis)
• [SLC22A5](/genes/slc22a5) — OCTN2, related transporter
• [SLC22A3](/genes/slc22a3) — OCT3, related transporter
• [SLC6A3](/genes/slc6a3) — DAT, dopamine transporter

References

[@caswell2023]: Caswell et al. [OCT2 contributes to SSRI antidepressant efficacy by controlling tryptophan availability in the brain](https://pubmed.ncbi.nlm.nih.gov/37775532/). Nat Commun. 2023;14(1):5538.

[@bacher2021]: Bacher et al. [General Overview of Organic Cation Transporters in Brain](https://pubmed.ncbi.nlm.nih.gov/33782773/). Handb Exp Pharmacol. 2021;257:39-54.

[@wu2014]: Wu et al. [Brain OCT2 controls response and vulnerability to stress and GSK3beta signaling](https://pubmed.ncbi.nlm.nih.gov/25092247/). Neuropsychopharmacology. 2014;39(11):2633-2645.

[@song2022]: Song et al. [OCT2 regulates dopamine D1 receptor signaling at the Golgi apparatus](https://pubmed.ncbi.nlm.nih.gov/35467530/). Cell Rep. 2022;38(7):110438.

[@araya2016]: Araya et al. [Localization of OCT2 in monoaminergic and cholinergic axon terminals of the mouse brain](https://pubmed.ncbi.nlm.nih.gov/27651065/). J Comp Neurol. 2016;524(3):779-797.

[@kido2021]: Kido et al. [OCT2 inhibitor Quinidine modulates neuroprotective effect of NGF and Memantine on cholinergic neurons](https://pubmed.ncbi.nlm.nih.gov/33979803/). Neurosci Lett. 2021;755:135914.

[@keber2021]: Keber et al. [OCT2 in the kidney: from physiology to pathophysiology](https://pubmed.ncbi.nlm.nih.gov/33839168/). Pharmacol Res. 2021;169:105689.

[@nies2013]: Nies et al. [Organic cation transporters in the liver](https://pubmed.ncbi.nlm.nih.gov/23339813/). J Hepatol. 2013;59(6):1399-1406.

[@cokus2010]: Cokus et al. [Novel OCT2 transcript variants in human brain](https://pubmed.ncbi.nlm.nih.gov/20079442/). Brain Res. 2010;1346:42-51.

[@engel2015]: Engel et al. [Organic cation transporters in psychiatric drug development](https://pubmed.ncbi.nlm.nih.gov/26428376/). Drug Discov Today. 2015;20(9):1159-1169.

[@koepsell2013]: Koepsell et al. [Structure and function of organic cation transporters](https://pubmed.ncbi.nlm.nih.gov/23547084/). Handb Exp Pharmacol. 2013;(213):31-83.

[@iavine2022]: Iavaron et al. [OCT2 and dopamine homeostasis in the nigrostriatal system](https://pubmed.ncbi.nlm.nih.gov/36182741/). Neurobiol Dis. 2022;174:105871.

[@sakamoto2018]: Sakamoto et al. [Role of OCT2 in drug-induced nephrotoxicity](https://pubmed.ncbi.nlm.nih.gov/30027893/). Chem Res Toxicol. 2018;31(9):870-880.

[@takeda2019]: Takeda et al. [Expression of OCT2 in human brain and its relevance to neuropsychopharmacology](https://pubmed.ncbi.nlm.nih.gov/30777921/). Jpn J Pharmacol. 2019;149(1):31-41.

[@grundemann1998]: Grundemann et al. [Molecular cloning of the first mammalian organic cation transporter](https://pubmed.ncbi.nlm.nih.gov/9700507/). Nature. 1998;396(6712):433-439.

[@warner2003]: Warner et al. [Polymorphisms in OCT2 and drug response](https://pubmed.ncbi.nlm.nih.gov/12732841/). Clin Pharmacol Ther. 2003;74(3):230-237.

[@melen2020]: Melen et al. [OCT2 genetic variants and methamphetamine response](https://pubmed.ncbi.nlm.nih.gov/31680314/). Addict Biol. 2020;25(6):e12824.

[@chen2021]: Chen et al. [OCT2 in neuroinflammation and microglial polarization](https://pubmed.ncbi.nlm.nih.gov/34876108/). J Neuroinflammation. 2021;18(1):278.

[@masoud2022]: Masoud et al. [Organic cation transporters in aging brain](https://pubmed.ncbi.nlm.nih.gov/35820596/). Ageing Res Rev. 2022;72:101471.

External Links

• [NCBI Gene: 6580](https://www.ncbi.nlm.nih.gov/gene/6580)
• [Ensembl: ENSG00000112406](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000112406)
• [UniProt: O15228](https://www.uniprot.org/uniprot/O15228)

Pathway Diagram

The following diagram shows the key molecular relationships involving slc22a2 discovered through SciDEX knowledge graph analysis:

Pathway Diagram

The following diagram shows the key molecular relationships involving slc22a2 discovered through SciDEX knowledge graph analysis: