SLC22A3 (Solute carrier family 22 member 3)

2015-05-01   Hasan Huseyin Kazan , Can Özen , Mesut Muyan 

Identity

HGNC
LOCATION
6q25.3
IMAGE
Atlas Image
LEGEND
Figure 1. Localization of human SLC22A3 gene on chromosome 6q26-q27 (as depicted in Verhaagh et al., 2009).IMAGE_FISH
LOCUSID
ALIAS
EMT,EMTH,OCT3
FUSION GENES

Abstract

Review on SLC22A3, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Note

SLC22A3 is one of three members of cation transporter genes located on chromosome 6. SLC22A3 is involved in the transportation of a variety of organic cations. Organic transporters have been included into the family of solute carrier proteins due to their homologies and third member of this family which was previously called organic cation transporter 3, OCT3, and the extraneuronal monoamine transporter, EMT, renamed as SLC22A3 (Verhaagh et al., 1999; Wieland et al., 2000; Verhaagh et al., 2001).
Atlas Image
Figure 2. Gene structure of human SLC22A3 (as depicted inWieland et al., 2000).

Description

The SLC22A3 gene consists of 11 exons and 10 introns, and encodes a 551 amino acid long membrane protein that comprises 12 predicted ?-helical transmembrane domains (TMDs). Intron/exon boundaries have the conserved gt/ag consensus splice sites (Figure 2). The exon 1 encodes N-terminus together with the first TMD and the exon 8 encodes TMD 10. The other SLC22A3 exons encode more than one TMDs (Wieland et al., 2000). SLC22A3 displays a structure conserved in members of solute carrier proteins (OCT1, OCT2, ORCTL2, ORCTL3, ORCTL4; Wieland et al., 2000) and in different organisms (rat, murine, mouse, and human; Burckhardt& Wolff, 2000; Wieland et al., 2000).

Transcription

It is reported that a large noncoding RNA (ncRNA), Air, silences cis-linked distal paternal Slc22a3 gene (mouse SLC22A3 gene) allele-specifically by interacting Slc22a3 promoter and H3K9 histone methyltransferase in placenta (Nagano et al, 2008). Studies indicate that the basal promoter of SLC22A3 contains a large CpG island which extends into exon 1, and abnormal methylation decreases SLC22A3 expression in human prostate cancer (Chen et al., 2013).

Proteins

Description

The SLC22A3 protein is composed of 551 amino acids with a 61 kDa molecular mass (Kekuda et al., 1998). The protein is predicted to be composed of 12 TMDs and both NH2 and COOH termini of the protein locate at the cytoplasmic site of the plasma membrane (Kekuda et al., 1998; Burckhardt& Wolff, 2000). There are three potential N-linked glycosylation sites (positions 72, 99 and 114) within a large extracellular loop (106 amino acids) located between TMDs 1 and 2. Another N-linked glycosylation site is localized at position 199 in an extracellular loop formed between TMDs 3 and 4. SLC22A3 also contains putative phosphorylation sites for protein kinase C (Ser-286, Thr-292 and Thr-459) and protein kinase A (Thr-346 and Thr-544) (Kekuda et al., 1998).

Expression

SLC22A3 is expressed in a wide range of tissues including the first-trimester and term placenta, skeletal muscle, prostate, liver, aorta, fetal lung, salivary gland, adrenal gland (Verhaagh et al., 1999), sympathetically innervated tissues (Lazar et al., 2003), heart, brain (Vialou et al., 2004; Chen et al., 2010), central nervous system (Zhu et al., 2012) and kidney (Wu et al., 2000).

Localisation

SLC22A3 is localized on the plasma membrane (Kekuda et al., 1998; Burckhardt& Wolff, 2000).

Function

SLC22A3 is a potential-sensitive organic cation transporter and activated by inside-negative membrane potential (Kekuda et al., 1998). The main function of the protein is to uptake and to eliminate clinically used drugs, endogenous organic cations (dopamine, norepinephrine and histamine; Wu et al., 2000) and toxic substances in the kidney, placenta and liver by uptake-2 transport system, which is the high-capacity and low-affinity transport system (Hayer-Zillgen et al. 2002; Vialou et al., 2004; Sakata et al., 2010). SLC22A3 uptakes catecholamines and neurotoxic organic cations in glial cells (Wieland et al., 2000). It also carries out the clearance of monoamines by co-localizing with other enzymes in placenta (Verhaagh et al., 2001). The mouse homolog Slc22a3 is shown to be involved in regulating salt-uptake (Vialou et al., 2004) and is a regulator of neurotransmission by controlling the transportation of dopamine, norepinephrine, 5-hydroxytriptamine, epinephrine and histamine in the central nervous system (Zhu et al., 2012). The activity of SLC22A3 is selectively inhibited by corticosterone, progesterone and 17?-estradiol, O-methylisoprenaline (OMI) and decynium22 (Hayer-Zillgen et al., 2002).

Homology

SLC22A3 shares homology with the other members of organic cation transporter OCT1 and OCT2; at amino acid sequence level, the identity ranges between 30-51% (Kekuda et al., 1998). SLC22A3 also shows conserved amino acid sequences in mammals (Burckhardt& Wolff, 2000; Wu et al., 2000).

Mutations

Note

It is reported that there are six single-nucleotide substitutions and one deletion within the core promoter, exonic and intronic sequences and 3 untranslated region without any amino acid changes in Caucasians, suggesting that the mutations would be as the result of demographic differences (Lazar et al., 2003). A non-synonymous substitution in SLC22A3 gene, Mel370Ile, may be related to obsessive-compulsive disorder (Lazar et al., 2008). Of the reported five nonsynonymous SNPs (T44M, A116S, T400I, A439V and G475S; NCBI dbSNP, http://ncbi.nlm.nih.gov/SNP; Sakata et al., 2010), A116, A439 and G475 are found only in the SLC22A3 gene while the others are also found in other organic cation transporter genes. The variations in the amino acid sequence result in a reduced substrate uptake and functionality (Sakata et al., 2010). It is also reported that T44M, P84P, A116S, R102R, T400I, A411A, L498L SNPs in the coding regions of SLC22A3, as well as SNPs in intronic regions, may result in alterations in substrate specificity (Chen et al., 2010).

Implicated in

Entity name
Hepatocellular carcinoma
Note
SLC22A3, as SLC22A1, is downregulated in human hepatocellular carcinoma. The downregulation of SLC22A3 is associated with tumor progression and poor patient survival (Heise et al. 2012).
Entity name
Prostate cancer
Note
Studies with 12 known risk polymorphisms in risk allele status for prostate tissue suggest that 4 of 12 prostate cancer risk variants are related to five transcripts, one of which is SLC22A3. Studies suggest that the expression of SLC22A3 is reduced in prostate cancer cells due to the aberrant methylation of the promoter region, an indication that the reduced level of SLC22A3 expression may be involved in the progression of prostate cancer (Chen et al., 2013).
Entity name
Renal cell carcinoma
Note
Kidneys are important for the excretion of xenobiotic compounds and consequently are highly susceptible for tumor development. Renal cell carcinomas are mainly resistant to chemotherapies, which appear to be dependent upon the expression of transporter proteins that include SLC22A3 (Shnitsar et al., 2009).
Entity name
Distal colon cancer
Note
Genome-wide studies suggest that the genetic variant rs7758229 in SLC22A3 is associated with colorectal cancer susceptibility in Japanese population (Cui et al, 2011), the same variant, on the other hand, shows no association for colorectal cancer risk in a Chinese cohort (Zhu et al., 2013).
Entity name
Coronary artery disease (CAD)
Note
Genome-wide haplotype association studies suggest that SLC22A3-LPAL2-LPA gene cluster constitutes a strong susceptibility locus for CAD (Tregouet et al., 2009).
Entity name
Methamphetamine (MAP) use disorder
Note
MAP is an amphetamine derivative and illicit psycho-stimulant. MAP dependence, an important social problem, is thought to be influenced by genetic factors. Due to the ability of SLC22A3 to transport MAP (Wu et al., 1998), it is suggested that polymorphisms in SLC22A3 gene may be correlated with MAP dependence (Aoyama et al., 2006).
Entity name
Obsessive-compulsive disorder (OCD)
Note
OCD is primarily linked with abnormalities in serotonergic system. The observations that genome-wide linkage of OCD (6q26) overlaps with SLC22A3 (6q26-q27) provides a support for a role of SLC22A3 in OCD. Two novel mutations, Met370Ile and -106/107delAG which cause 40% reduction in norepinephrine transport in patients, could underlie the modulatory role of SLC22A3 in OCD (Lazar et al., 2008).
Entity name
Depression
Note
Clearance of neurotransmitters for the homeodynamic regulation of the central nervous system is mediated by uptake-1 and uptake-2 systems. The uptake-2 is a low-affinity and high-capacity system within which SLC22A3 plays a significant role (Schildkraut and Mooney, 2004). SLC22A3 transports various neurotransmitters including dopamine, norepinephrine, epinephrine, 5-hydroxytryptamine and histamine (Wu et al., 2000). Anti-depressants currently used in clinics include selective 5-HT and 5-HT-NE inhibitors. Studies suggest that the inhibition of SLC22A3-mediated neurotransmitter uptake is a critical contributor for the effects of antidepressants, underlying the importance of SLC22A3 in depression progression and protection (Baganz et al., 2008; Mooney et al., 2008; Zhu et al., 2012).

Bibliography

Pubmed IDLast YearTitleAuthors
170101312006Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder.Aoyama N et al
108369732000Structure of renal organic anion and cation transporters.Burckhardt G et al
222315672013Genetic and epigenetic regulation of the organic cation transporter 3, SLC22A3.Chen L et al
208592432010Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin.Chen L et al
212422602011Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population.Cui R et al
121106072002Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3.Hayer-Zillgen M et al
224396942012Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance.Heise M et al
96326451998Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta.Kekuda R et al
127684392003Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3).Lazar A et al
174778852008Novel mutations of the extraneuronal monoamine transporter gene in children and adolescents with obsessive-compulsive disorder.Lazar A et al
177278822008Enhanced norepinephrine output during long-term desipramine treatment: a possible role for the extraneuronal monoamine transporter (SLC22A3).Mooney JJ et al
189888102008The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin.Nagano T et al
205625192010Functional analysis of human organic cation transporter OCT3 (SLC22A3) polymorphisms.Sakata T et al
151216582004Toward a rapidly acting antidepressant: the normetanephrine and extraneuronal monoamine transporter (uptake 2) hypothesis.Schildkraut JJ et al
191903422009Expression of human organic cation transporter 3 in kidney carcinoma cell lines increases chemosensitivity to melphalan, irinotecan, and vincristine.Shnitsar V et al
191986112009Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease.Trégouët DA et al
111188982001The extraneuronal monoamine transporter Slc22a3/Orct3 co-localizes with the Maoa metabolizing enzyme in mouse placenta.Verhaagh S et al
150287792004Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation.Vialou V et al
111291042000Analysis of the gene structure of the human (SLC22A3) and murine (Slc22a3) extraneuronal monoamine transporter.Wieland A et al
109669242000Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney.Wu X et al
98300221998Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain.Wu X et al
223428162012Evaluation of organic cation transporter 3 (SLC22A3) inhibition as a potential mechanism of antidepressant action.Zhu HJ et al
235550062013Genetic variant rs7758229 in 6q26-q27 is not associated with colorectal cancer risk in a Chinese population.Zhu L et al

Other Information

Locus ID:

NCBI: 6581
MIM: 604842
HGNC: 10967
Ensembl: ENSG00000146477

Variants:

dbSNP: 6581
ClinVar: 6581
TCGA: ENSG00000146477
COSMIC: SLC22A3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000146477ENST00000275300O75751

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Choline metabolism in cancerKEGGhsa05231
Choline metabolism in cancerKEGGko05231
Transmembrane transport of small moleculesREACTOMER-HSA-382551
SLC-mediated transmembrane transportREACTOMER-HSA-425407
Transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compoundsREACTOMER-HSA-425366
Organic cation/anion/zwitterion transportREACTOMER-HSA-549132
Organic cation transportREACTOMER-HSA-549127
MetabolismREACTOMER-HSA-1430728
Abacavir transport and metabolismREACTOMER-HSA-2161522
Abacavir transmembrane transportREACTOMER-HSA-2161517

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA133822447catecholaminesChemicalClinicalAnnotationassociatedPK20859243
PA166123207overall survivalDiseaseVariantAnnotationassociatedPD
PA445218Pancreatic NeoplasmsDiseaseVariantAnnotationassociatedPD
PA450163lamivudineChemicalPathwayassociated
PA450395metforminChemicalClinicalAnnotation, MultilinkAnnotation, PathwayassociatedPKPD20859243, 22722338, 25920679

References

Pubmed IDYearTitleCitations
191986112009Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease.153
191986112009Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease.153
195911962009Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver.97
195911962009Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver.97
230711042012Expression of Wnt3 activates Wnt/β-catenin pathway and promotes EMT-like phenotype in trastuzumab-resistant HER2-overexpressing breast cancer cells.67
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
193184322009Generalizability of associations from prostate cancer genome-wide association studies in multiple populations.60
210715402011Validation of genome-wide prostate cancer associations in men of African descent.51
227304612012Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis.51
199024742010Replication of prostate cancer risk loci on 8q24, 11q13, 17q12, 19q33, and Xp11 in African Americans.39

Citation

Hasan Huseyin Kazan ; Can Özen ; Mesut Muyan

SLC22A3 (Solute carrier family 22 member 3)

Atlas Genet Cytogenet Oncol Haematol. 2015-05-01

Online version: http://atlasgeneticsoncology.org/gene/51061/slc22a3