Details for: SLC22A2

Gene ID: 6582

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: SLC22A2

Ensembl ID: ENSG00000112499

Description: solute carrier family 22 member 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • epithelial cell of proximal tubule CL0002306
    CSI 12.15
    rCSI 29.68%
    PRS 96.68
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 5.84
    rCSI 8.28%
    PRS 98.37
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 5.67
    rCSI 14.77%
    PRS 99.38
  • parietal epithelial cell CL1000452
    CSI 3.95
    rCSI 10.56%
    PRS 97.9
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 3.34
    rCSI 8.65%
    PRS 98.53
  • renal principal cell CL0005009
    CSI 2.91
    rCSI 7.55%
    PRS 98.76
  • kidney loop of Henle thick ascending limb epithelial cell CL1001106
    CSI 2.38
    rCSI 20.53%
    PRS 97.3

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [SLC22A2](/details-gene/6582), also known as Organic Cation Transporter 2 (OCT2), is a protein-coding gene located on chromosome 6q25.3. It belongs to the solute carrier family and functions as a polyspecific transporter responsible for the transport of a wide range of endogenous and exogenous organic cations. This includes neurotransmitters (dopamine, serotonin, norepinephrine), metabolites (creatinine), and numerous drugs and xenobiotics ([Link](https://pubmed.ncbi.nlm.nih.gov/9260930/)). **Overall**, expression data reveals that [SLC22A2](/details-gene/6582) is overwhelmingly and specifically expressed in the kidney, where it serves as a defining marker for the [epithelial cell of proximal tubule](/details-cell/CL0002306). Its primary physiological role is in the basolateral uptake of organic cations from the blood into tubular cells for subsequent secretion into the urine, a critical step in renal clearance ([Link](https://doi.org/10.1023/b:pham.0000029286.45788.ad)). Its function is clinically significant, influencing the pharmacokinetics and nephrotoxicity of many therapeutic agents ([OMIM: 602608](https://omim.org/entry/602608)). ## Cellular Roles and Expression Landscape The expression profile of [SLC22A2](/details-gene/6582) firmly establishes its central role in renal physiology. The gene shows the highest significance and expression abundance in the [epithelial cell of proximal tubule](/details-cell/CL0002306) (CSI: 12.15), highlighting its function as a primary workhorse for transport in this segment of the nephron. Significant expression is also observed in other epithelial components of the kidney, including the [kidney loop of Henle thin descending limb epithelial cell](/details-cell/CL1001111) (CSI: 5.84), [parietal epithelial cell](/details-cell/CL1000452) (CSI: 3.95), and [renal principal cell](/details-cell/CL0005009) (CSI: 2.91). This collective expression pattern underscores its integral function across different parts of the renal tubule system in maintaining clearance and homeostasis. Interestingly, a notable expression signature is also found in [kidney interstitial alternatively activated macrophage](/details-cell/CL1000695) (CSI: 5.67). This suggests a potential secondary role for [SLC22A2](/details-gene/6582) beyond epithelial transport, possibly related to the clearance of cationic molecules or modulation of the immune microenvironment within the kidney interstitium. While initially identified in the kidney, studies have also documented its expression in other tissues, including the brain and bronchial epithelium, where it may contribute to neurotransmitter transport and acetylcholine release, respectively ([Link](https://doi.org/10.1124/mol.54.2.342/), [Link](https://doi.org/10.1165/rcmb.2004-0363oc)). ## Pathways and Molecular Function Functionally, [SLC22A2](/details-gene/6582) is annotated as a key player in transmembrane transport processes. Its molecular function is defined by its broad substrate specificity, encompassing [Organic cation transmembrane transporter activity](/details-ontology/GO:0015101), [Neurotransmitter transmembrane transporter activity](/details-ontology/GO:0005326), and [Xenobiotic transmembrane transporter activity](/details-ontology/GO:0042910). The gene is involved in a multitude of biological processes, primarily centered on the transport of small molecules such as neurotransmitters ([Dopamine transport](/details-ontology/GO:0015872), [Serotonin transport](/details-ontology/GO:0006837)), metabolites, and foreign compounds ([Xenobiotic transport](/details-ontology/GO:0042908)). This functional profile is consistent with its involvement in Reactome pathways such as [Organic cation transport](/details-pathway/R-HSA-549127) and [Slc-mediated transmembrane transport](/details-pathway/R-HSA-425407). Its role extends to pharmacology, as highlighted by its inclusion in the [Drug adme](/details-pathway/R-HSA-9748784) pathway, which details the absorption, distribution, metabolism, and excretion of drugs. The transporter's localization to the [Basolateral plasma membrane](/details-ontology/GO:0016323) of polarized epithelial cells, particularly in the kidney, is critical for its function in moving substrates from the bloodstream into the cell for renal excretion. This mechanism is crucial for the clearance of drugs like cisplatin, and its activity directly mediates the nephrotoxicity associated with such compounds ([Link](https://doi.org/10.1016/s0002-9440(10)61234-5)). ## Research Directions The well-defined role of [SLC22A2](/details-gene/6582) in drug disposition and renal physiology presents several avenues for future investigation, particularly concerning pharmacogenomics and kidney disease. **Proposed Hypotheses:** 1. **Pharmacogenomic Variability:** Genetic variants in [SLC22A2](/details-gene/6582) are likely to be significant predictors of inter-individual variability in both the efficacy and toxicity of renally-cleared cationic drugs (e.g., metformin, cisplatin). Variants that reduce transporter function may lead to higher systemic drug exposure and reduced nephrotoxicity, whereas gain-of-function variants could enhance renal clearance but increase the risk of drug accumulation in tubular cells. 2. **Role in Chronic Kidney Disease (CKD) Pathogenesis:** Dysregulation or reduced expression of [SLC22A2](/details-gene/6582) may contribute to the progression of CKD by impairing the clearance of endogenous uremic toxins. This impaired transport could lead to the systemic accumulation of these toxins, exacerbating inflammation and fibrosis. 3. **Immunomodulatory Function in Kidney Macrophages:** The expression of [SLC22A2](/details-gene/6582) in [kidney interstitial alternatively activated macrophage](/details-cell/CL1000695) suggests a role in modulating the local immune environment. It may function to clear inflammatory cationic molecules or transport substrates that influence macrophage polarization and function, thereby impacting the balance between renal injury and repair. **Experimental Approach:** To test the hypothesis regarding the immunomodulatory function of [SLC22A2](/details-gene/6582) in kidney macrophages (Hypothesis 3), a myeloid-specific conditional knockout mouse model (e.g., *Slc22a2*fl/fl; Lyz2-Cre) could be generated. Following induction of kidney injury (e.g., via ischemia-reperfusion or an aristolochic acid nephropathy model), the inflammatory response and subsequent fibrosis could be compared between knockout and wild-type mice. Key analyses would include single-cell RNA sequencing of kidney immune infiltrates to assess macrophage transcriptional states, flow cytometry to quantify macrophage polarization (M1/M2 markers), and histological analysis to measure fibrosis and tissue damage. This approach would elucidate whether [SLC22A2](/details-gene/6582) in macrophages plays a protective or pathogenic role during kidney injury. **Therapeutic Potential:** [SLC22A2](/details-gene/6582) represents a compelling therapeutic target for modulating drug pharmacokinetics and mitigating toxicity. **Inhibition** of the transporter could be a valuable strategy for nephroprotection. Co-administration of a specific [SLC22A2](/details-gene/6582) inhibitor with substrates known for nephrotoxicity, such as cisplatin, could reduce their uptake into proximal tubule cells, thereby decreasing localized damage without compromising systemic therapeutic efficacy. Conversely, developing molecules that **enhance** or **activate** [SLC22A2](/details-gene/6582) transport activity could represent a novel therapeutic approach for certain metabolic disorders or CKD, by promoting the clearance of harmful endogenous cationic toxins from the body.

Genular Protein ID: 3467177422

Symbol: S22A2_HUMAN

Name: N/A

UniProtKB Accession Codes:

O15244 Q5T7Q6 Q6PIQ8 Q8NG62 Q9NQB9

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 20 ChEMBL 1 DNASU 1 DisGeNET 1 DrugBank 116 DrugCentral 1 EMBL 8 EMDB 1 Ensembl 1 ExpressionAtlas 1 GO 56 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 Reactome 5 RefSeq 1 Rhea 22 SABIO-RK 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9260930

Title: Cloning and characterization of two human polyspecific organic cation transporters.

PubMed ID: 9260930

DOI: 10.1089/dna.1997.16.871

PubMed ID: 12089365

Title: cDNA cloning, functional characterization, and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney.

PubMed ID: 12089365

DOI: 10.1097/01.asn.0000019413.78751.46

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 14574404

Title: The DNA sequence and analysis of human chromosome 6.

PubMed ID: 14574404

DOI: 10.1038/nature02055

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 10942111

Title: Gene structures of the human non-neuronal monoamine transporters EMT and OCT2.

PubMed ID: 10942111

DOI: 10.1007/s004390000309

PubMed ID: 9687576

Title: Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine.

PubMed ID: 9687576

DOI: 10.1124/mol.54.2.342

PubMed ID: 11912245

Title: Gene expression levels and immunolocalization of organic ion transporters in the human kidney.

PubMed ID: 11912245

DOI: 10.1681/asn.v134866

PubMed ID: 12395288

Title: The organic cation transporters rOCT1 and hOCT2 are inhibited by cGMP.

PubMed ID: 12395288

DOI: 10.1007/s00232-002-1023-7

PubMed ID: 11907186

Title: Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins.

PubMed ID: 11907186

DOI: 10.1124/jpet.301.1.293

PubMed ID: 12538837

Title: Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2).

PubMed ID: 12538837

DOI: 10.1124/jpet.102.044404

PubMed ID: 15496291

Title: Different transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A).

PubMed ID: 15496291

DOI: 10.1016/j.ejphar.2004.09.032

PubMed ID: 15212162

Title: Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney.

PubMed ID: 15212162

DOI: 10.1023/b:pham.0000029286.45788.ad

PubMed ID: 16314463

Title: Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2.

PubMed ID: 16314463

DOI: 10.1016/s0002-9440(10)61234-5

PubMed ID: 15817714

Title: Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium.

PubMed ID: 15817714

DOI: 10.1165/rcmb.2004-0363oc

PubMed ID: 16263091

Title: Drug specificity and intestinal membrane localization of human organic cation transporters (OCT).

PubMed ID: 16263091

DOI: 10.1016/j.bcp.2005.09.011

PubMed ID: 16272756

Title: Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1.

PubMed ID: 16272756

DOI: 10.2133/dmpk.20.379

PubMed ID: 16006492

Title: A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters.

PubMed ID: 16006492

DOI: 10.1124/jpet.105.088104

PubMed ID: 15783073

Title: Metformin transport by renal basolateral organic cation transporter hOCT2.

PubMed ID: 15783073

DOI: 10.1007/s11095-004-1193-3

PubMed ID: 16394027

Title: Characterization of regulatory mechanisms and states of human organic cation transporter 2.

PubMed ID: 16394027

DOI: 10.1152/ajpcell.00622.2005

PubMed ID: 16951202

Title: Organic cation transporters are determinants of oxaliplatin cytotoxicity.

PubMed ID: 16951202

DOI: 10.1158/0008-5472.can-06-0769

PubMed ID: 17072098

Title: Interactions of fluoroquinolone antibacterials, DX-619 and levofloxacin, with creatinine transport by renal organic cation transporter hOCT2.

PubMed ID: 17072098

DOI: 10.2133/dmpk.21.432

PubMed ID: 16914559

Title: Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family).

PubMed ID: 16914559

DOI: 10.1124/jpet.106.110346

PubMed ID: 16581093

Title: Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain.

PubMed ID: 16581093

DOI: 10.1016/j.neuropharm.2006.01.005

PubMed ID: 17393420

Title: The organic cation transporters (OCT1, OCT2, EMT) and the plasma membrane monoamine transporter (PMAT) show differential distribution and cyclic expression pattern in human endometrium and early pregnancy decidua.

PubMed ID: 17393420

DOI: 10.1002/mrd.20697

PubMed ID: 21128598

Title: OCT2 and MATE1 provide bidirectional agmatine transport.

PubMed ID: 21128598

DOI: 10.1021/mp100180a

PubMed ID: 24961373

Title: OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin.

PubMed ID: 24961373

DOI: 10.1073/pnas.1314939111

PubMed ID: 26979622

Title: A phosphotyrosine switch regulates organic cation transporters.

PubMed ID: 26979622

DOI: 10.1038/ncomms10880

PubMed ID: 35307651

Title: Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier.

PubMed ID: 35307651

DOI: 10.1124/dmd.121.000748

PubMed ID: 12142729

Title: Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function.

PubMed ID: 12142729

DOI: 10.1097/00008571-200207000-00007

PubMed ID: 17111267

Title: Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin.

PubMed ID: 17111267

DOI: 10.1007/s10038-006-0087-0

PubMed ID: 17460754

Title: Identification of the endogenous key substrates of the human organic cation transporter OCT2 and their implication in function of dopaminergic neurons.

PubMed ID: 17460754

DOI: 10.1371/journal.pone.0000385

Sequence Information:

  • Length: 555
  • Mass: 62581
  • Checksum: 06528F9519CE211E
  • Sequence:
    • MPTTVDDVLE HGGEFHFFQK QMFFLLALLS ATFAPIYVGI VFLGFTPDHR CRSPGVAELS 
LRCGWSPAEE LNYTVPGPGP AGEASPRQCR RYEVDWNQST FDCVDPLASL DTNRSRLPLG 
PCRDGWVYET PGSSIVTEFN LVCANSWMLD LFQSSVNVGF FIGSMSIGYI ADRFGRKLCL 
LTTVLINAAA GVLMAISPTY TWMLIFRLIQ GLVSKAGWLI GYILITEFVG RRYRRTVGIF 
YQVAYTVGLL VLAGVAYALP HWRWLQFTVS LPNFFFLLYY WCIPESPRWL ISQNKNAEAM 
RIIKHIAKKN GKSLPASLQR LRLEEETGKK LNPSFLDLVR TPQIRKHTMI LMYNWFTSSV 
LYQGLIMHMG LAGDNIYLDF FYSALVEFPA AFMIILTIDR IGRRYPWAAS NMVAGAACLA 
SVFIPGDLQW LKIIISCLGR MGITMAYEIV CLVNAELYPT FIRNLGVHIC SSMCDIGGII 
TPFLVYRLTN IWLELPLMVF GVLGLVAGGL VLLLPETKGK ALPETIEEAE NMQRPRKNKE 
KMIYLQVQKL DIPLN