Details for: SLC22A6

Gene ID: 9356

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: SLC22A6

Ensembl ID: ENSG00000197901

Description: solute carrier family 22 member 6

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 8.02
    rCSI 19.58%
    PRS 98
  • retinal pigment epithelial cell CL0002586
    CSI 2.46
    rCSI 4.88%
    PRS 98.64
  • epithelial cell of proximal tubule segment 3 CL4030011
    CSI 2.1
    rCSI 16.71%
    PRS 98.96
  • parietal epithelial cell CL1000452
    CSI 1.54
    rCSI 4.12%
    PRS 98.94
  • kidney proximal convoluted tubule epithelial cell CL1000838
    CSI 0.93
    rCSI 9.85%
    PRS 99.23

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

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  • Node Color (Target Cell CSI, relative to current network):
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  • Node Size: Proportional to Target Cell CSI magnitude
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  • 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 [SLC22A6](/details-gene/9356), or Solute Carrier Family 22 Member 6, encodes the protein Organic Anion Transporter 1 (OAT1). This protein is a crucial transmembrane transporter primarily responsible for the uptake of a wide range of organic anions from the blood into renal proximal tubule cells, facilitating their secretion into urine. **Overall**, expression data reveals that [SLC22A6](/details-gene/9356) is a highly specific and abundant marker for the [epithelial cell of proximal tubule](/details-cell/CL0002306) (CSI: 8.02), underscoring its central role in renal clearance of endogenous metabolites, drugs, and environmental toxins. Its function is essential for detoxification and maintaining metabolic homeostasis. ## Cellular Roles and Expression Landscape The expression profile of [SLC22A6](/details-gene/9356) demonstrates remarkable tissue and cell-type specificity. The gene's significance is overwhelmingly concentrated in the kidney, where it serves as a defining feature of renal epithelial cells. * **Primary Functional Niche:** The highest significance score for [SLC22A6](/details-gene/9356) is found in the [epithelial cell of proximal tubule](/details-cell/CL0002306) (CSI: 8.02), with related cell types such as [epithelial cell of proximal tubule segment 3](/details-cell/CL4030011) and [kidney proximal convoluted tubule epithelial cell](/details-cell/CL1000838) also showing high significance. This establishes the gene's primary role in the first step of active tubular secretion, a key process in renal physiology. Its high expression is consistent with its function as a "workhorse" transporter responsible for clearing a vast array of substances from the bloodstream. * **Secondary Expression Sites:** A notable secondary site of significant expression is the [retinal pigment epithelial cell](/details-cell/CL0002586) (CSI: 2.46). This suggests a potential, albeit less characterized, role in transporting organic anions across the blood-retina barrier, possibly for waste clearance or nutrient exchange within the eye. The highly restricted expression pattern highlights [SLC22A6](/details-gene/9356) as a specialized transporter, with its biological impact largely confined to epithelial barriers involved in secretion and filtration, particularly within the kidney. ## Pathways and Molecular Function Functionally, [SLC22A6](/details-gene/9356) is an antiporter located on the basolateral membrane of epithelial cells ([GO:0016323](https://www.ebi.ac.uk/QuickGO/term/GO:0016323)). It mediates the uptake of organic anions in exchange for intracellular dicarboxylates, such as alpha-ketoglutarate ([GO:0015742](https://www.ebi.ac.uk/QuickGO/term/GO:0015742)). This activity is a cornerstone of several key biological processes and pathways. * **Transport and Secretion:** The gene is centrally involved in [Organic anion transport (GO:0015711)](https://www.ebi.ac.uk/QuickGO/term/GO:0015711) and more specifically, [Renal tubular secretion (GO:0097254)](https://www.ebi.ac.uk/QuickGO/term/GO:0097254). This is further captured by its annotation in Reactome pathways like [Organic anion transport (R-HSA-561048)](https://reactome.org/content/detail/R-HSA-561048) and [Slc-mediated transmembrane transport (R-HSA-425407)](https://reactome.org/content/detail/R-HSA-425407). * **Substrate Specificity:** OAT1 exhibits broad substrate specificity, a feature critical for its role in detoxification. It transports not only endogenous metabolites like prostaglandins ([Link](https://pubmed.ncbi.nlm.nih.gov/11907186/)) and uremic toxins ([Link](https://pubmed.ncbi.nlm.nih.gov/14675047/)), but also a wide array of clinically relevant drugs and xenobiotics. This includes antiviral medications like cidofovir and adefovir ([Link](https://pubmed.ncbi.nlm.nih.gov/10462545/)), mycotoxins such as ochratoxin A ([Link](https://pubmed.ncbi.nlm.nih.gov/11669456/)), and various other compounds, as demonstrated in numerous cloning and characterization studies ([Link](https://pubmed.ncbi.nlm.nih.gov/9887087/), [Link](https://pubmed.ncbi.nlm.nih.gov/9950961/)). This broad capacity for [Xenobiotic transport (GO:0042908)](https://www.ebi.ac.uk/QuickGO/term/GO:0042908) makes it a key determinant of drug pharmacokinetics and a site for potential drug-drug interactions. ## Research Directions The well-defined role of [SLC22A6](/details-gene/9356) in renal drug handling and its high specificity make it a critical subject for pharmacogenomics and toxicology research. Future investigations could focus on its genetic variability and secondary physiological roles. **Proposed Testable Hypotheses:** 1. Genetic polymorphisms in the [SLC22A6](/details-gene/9356) gene lead to clinically significant variations in transport efficiency, altering individual susceptibility to drug-induced nephrotoxicity from substrates like NSAIDs, methotrexate, or certain antiviral agents. 2. The expression of [SLC22A6](/details-gene/9356) in the [retinal pigment epithelial cell](/details-cell/CL0002586) is critical for clearing metabolic byproducts (e.g., all-trans-retinal derivatives) from the subretinal space, and its dysfunction may contribute to the pathogenesis of retinal degenerative diseases. **Key Experimental Approach:** To test the first hypothesis regarding pharmacogenomic impact, one could employ a multi-pronged approach. First, identify common and rare non-synonymous variants of [SLC22A6](/details-gene/9356) from human population databases. These variants could be engineered into a stable cell line (e.g., HEK293) to perform *in vitro* transport assays using radiolabeled or fluorescent substrates (e.g., p-aminohippurate, cidofovir). This would directly measure functional differences in uptake kinetics (Vmax, Km) between the wild-type and variant transporters. Subsequently, a humanized mouse model with a null *Slc22a6* background could be generated to express specific human variants. Administration of a known nephrotoxic OAT1 substrate to these mice, followed by analysis of kidney function markers (serum creatinine, BUN) and histology, would provide *in vivo* evidence of how these variants affect drug disposition and toxicity. **Therapeutic Potential:** [SLC22A6](/details-gene/9356) is not a direct therapeutic target for activation but is a major target for **inhibition**. Its activity is a primary driver of nephrotoxicity for many drugs that accumulate in proximal tubule cells. Therefore, co-administering an OAT1 inhibitor (e.g., probenecid) is a clinically established strategy to reduce the renal clearance and associated toxicity of certain drugs, such as the antiviral cidofovir. Understanding the interaction of new chemical entities with OAT1 is a mandatory step in preclinical drug development to predict and mitigate potential drug-drug interactions and adverse renal events. The high specificity of its expression to the kidney makes it an ideal target for modulators designed to have localized effects with minimal systemic side effects.

Genular Protein ID: 2532278410

Symbol: S22A6_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q4U2R8 A8MY93 B2D0R6 O95187 O95742 Q7LDA0 Q8N192 Q9NQA6 Q9NQC2 Q9UBG6 Q9UEQ8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 4 CDD 1 CTD 1 ChEBI 26 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 156 DrugCentral 1 EMBL 16 Ensembl 4 ExpressionAtlas 1 GO 24 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 4 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 4 RNAct 1 Reactome 1 RefSeq 4 Rhea 13 SABIO-RK 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9762842

Title: Cloning of a human renal p-aminohippurate transporter, hROAT1.

PubMed ID: 9762842

DOI: 10.1159/000025863

PubMed ID: 9887087

Title: Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney.

PubMed ID: 9887087

DOI: 10.1152/ajprenal.1999.276.1.f122

PubMed ID: 9950961

Title: Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C.

PubMed ID: 9950961

DOI: 10.1152/ajprenal.1999.276.2.f295

PubMed ID: 10049739

Title: Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT1 and hOAT3).

PubMed ID: 10049739

DOI: 10.1006/bbrc.1998.9978

PubMed ID: 10462545

Title: The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1.

PubMed ID: 10462545

DOI: 10.1124/mol.56.3.570

PubMed ID: 10964714

Title: Genomic structure and in vivo expression of the human organic anion transporter 1 (hOAT1) gene.

PubMed ID: 10964714

DOI: 10.1006/bbrc.2000.3230

PubMed ID: 16554811

Title: Human chromosome 11 DNA sequence and analysis including novel gene identification.

PubMed ID: 16554811

DOI: 10.1038/nature04632

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: 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: 12538807

Title: Interaction of cysteine conjugates with human and rabbit organic anion transporter 1.

PubMed ID: 12538807

DOI: 10.1124/jpet.102.043455

PubMed ID: 11669456

Title: Characterization of ochratoxin A transport by human organic anion transporters.

PubMed ID: 11669456

DOI: 10.1016/s0024-3205(01)01296-6

PubMed ID: 14749323

Title: Role of glycosylation in the organic anion transporter OAT1.

PubMed ID: 14749323

DOI: 10.1074/jbc.m400197200

PubMed ID: 15145940

Title: Critical amino acid residues in transmembrane domain 1 of the human organic anion transporter hOAT1.

PubMed ID: 15145940

DOI: 10.1074/jbc.m404686200

PubMed ID: 14675047

Title: Characterization of uremic toxin transport by organic anion transporters in the kidney.

PubMed ID: 14675047

DOI: 10.1111/j.1523-1755.2004.00354.x

PubMed ID: 15644426

Title: Transport of the natural sweetener stevioside and its aglycone steviol by human organic anion transporter (hOAT1; SLC22A6) and hOAT3 (SLC22A8).

PubMed ID: 15644426

DOI: 10.1124/jpet.104.080366

PubMed ID: 17038320

Title: A three-dimensional model of human organic anion transporter 1: aromatic amino acids required for substrate transport.

PubMed ID: 17038320

DOI: 10.1074/jbc.m608834200

PubMed ID: 17502342

Title: Human organic anion transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) transport edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and its sulfate conjugate.

PubMed ID: 17502342

DOI: 10.1124/dmd.106.013912

PubMed ID: 22108572

Title: Interaction and transport of kynurenic acid via human organic anion transporters hOAT1 and hOAT3.

PubMed ID: 22108572

DOI: 10.1016/j.phrs.2011.11.003

PubMed ID: 23832370

Title: Transport of xanthurenic acid by rat/human organic anion transporters OAT1 and OAT3.

PubMed ID: 23832370

DOI: 10.1271/bbb.130178

PubMed ID: 26377792

Title: Human organic anion transporter 2 is distinct from organic anion transporters 1 and 3 with respect to transport function.

PubMed ID: 26377792

DOI: 10.1152/ajprenal.00140.2015

PubMed ID: 28534121

Title: Organic anion transporters, OAT1 and OAT3, are crucial biopterin transporters involved in bodily distribution of tetrahydrobiopterin and exclusion of its excess.

PubMed ID: 28534121

DOI: 10.1007/s11010-017-3060-7

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: 15914676

Title: Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6).

PubMed ID: 15914676

DOI: 10.1124/jpet.105.084301

PubMed ID: 16164626

Title: Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)].

PubMed ID: 16164626

DOI: 10.1111/j.1523-1755.2005.00612.x

Sequence Information:

  • Length: 563
  • Mass: 61816
  • Checksum: 74AD3EA2678032E4
  • Sequence:
    • MAFNDLLQQV GGVGRFQQIQ VTLVVLPLLL MASHNTLQNF TAAIPTHHCR PPADANLSKN 
GGLEVWLPRD RQGQPESCLR FTSPQWGLPF LNGTEANGTG ATEPCTDGWI YDNSTFPSTI 
VTEWDLVCSH RALRQLAQSL YMVGVLLGAM VFGYLADRLG RRKVLILNYL QTAVSGTCAA 
FAPNFPIYCA FRLLSGMALA GISLNCMTLN VEWMPIHTRA CVGTLIGYVY SLGQFLLAGV 
AYAVPHWRHL QLLVSAPFFA FFIYSWFFIE SARWHSSSGR LDLTLRALQR VARINGKREE 
GAKLSMEVLR ASLQKELTMG KGQASAMELL RCPTLRHLFL CLSMLWFATS FAYYGLVMDL 
QGFGVSIYLI QVIFGAVDLP AKLVGFLVIN SLGRRPAQMA ALLLAGICIL LNGVIPQDQS 
IVRTSLAVLG KGCLAASFNC IFLYTGELYP TMIRQTGMGM GSTMARVGSI VSPLVSMTAE 
LYPSMPLFIY GAVPVAASAV TVLLPETLGQ PLPDTVQDLE SRWAPTQKEA GIYPRKGKQT 
RQQQEHQKYM VPLQASAQEK NGL