Alternative titles; symbols
HGNC Approved Gene Symbol: SLC22A3
Cytogenetic location: 6q25.3 Genomic coordinates (GRCh38): 6:160,348,378-160,452,577 (from NCBI)
Polyspecific organic cation transporters in the liver, kidney, and intestine are critical for elimination of many endogenous amines as well as a wide array of drugs and environmental toxins.
By PCR using degenerate oligonucleotides corresponding to common sequence motifs of amphiphilic solute facilitators (e.g., SLC22A1; 602607) on cDNA from a human kidney carcinoma cell line, Grundemann et al. (1998) isolated a cDNA encoding SLC22A3, which they termed 'extraneuronal transporter for monoamine transmitters,' or EMT. The SLC22A3 gene encodes a deduced 556-amino acid protein containing 12 transmembrane segments. Expression analysis showed uptake of known catecholamine substrates by SLC22A3. RT-PCR analysis detected SLC22A3 expression in brain cortex, heart, and liver.
By searching an EST database with the mouse Slc22a3 sequence as the probe, Verhaagh et al. (1999) identified human ESTs encoding SLC22A3. Northern blot analysis detected high-level expression of a 3.6-kb SLC22A3 transcript in first-trimester and term placenta, skeletal muscle, prostate, aorta, liver, fetal lung, salivary gland, and adrenal gland. Moderate to low expression was detected in uterus, ovary, kidney, lymph node, lung, trachea, and fetal liver, and no expression was detected in brain, pancreas, pituitary gland, spleen, peripheral leukocytes, fetal brain, fetal spleen, and fetal thymus.
Wu et al. (1998) showed that recombinant rat Oct3 can transport a wide variety of cationic neurotoxins and neurotransmitters, including 1-methyl-4-phenylpyridinium ion (MPP+) and dopamine. Oct3 was inhibited by several steroids, with beta-estradiol the most potent inhibitor. The authors stated that the transport characteristics and steroid sensitivity of Oct3 provide strong evidence for its molecular identity as the extraneuronal monoamine transporter (uptake-2). Northern blot analysis detected Oct3 expression in a number of rat tissues, including brain. In situ hybridization of rat brain showed that Oct3 is widely expressed in the brain, including in the hippocampus, cerebellum, and cerebral cortex. Wu et al. (1998) suggested that OCT3 plays a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.
A bidirectional silencer for a 400-kb region that contains 3 imprinted, maternally expressed protein-coding genes (IGF2R, 147280; SLC22A2, 602608; SLC22A3) has been shown by targeted deletion to be located in a sequence of 3.7 kb, which also contains the promoter for the imprinted, paternally expressed noncoding Air RNA. Expression of Air is correlated with repression of all 3 genes on the paternal allele; however, Air RNA overlaps just 1 of these genes in an antisense orientation. By inserting a polyadenylation signal that truncates 96% of the RNA transcript, Sleutels et al. (2002) demonstrated that Air RNA is required for silencing. The truncated Air allele maintains imprinted expression and methylation of the Air promoter, but shows complete loss of silencing of the IGF2R/SLC22A2/SLC22A3 gene cluster on the paternal chromosome. Sleutels et al. (2002) concluded that noncoding RNAs have an active role in genomic imprinting.
Nagano et al. (2008) demonstrated that Air interacts with the Slc22a3 promoter chromatin and the H3K9 histone methyltransferase G9a (604599) in placenta. Air accumulates at the Slc22a3 promoter in correlation with localized H3K9 methylation and transcriptional repression. Genetic ablation of G9a results in nonimprinted, biallelic transcription of Slc22a3. Truncated Air fails to accumulate at the Slc22a3 promoter, which results in reduced G9a recruitment and biallelic transcription. Nagano et al. (2008) concluded that Air, and potentially other large noncoding RNAs, target repressive histone-modifying activities through molecular interaction with specific chromatin domains to epigenetically silence transcription.
Grundemann and Schomig (2000) isolated the human SLC22A3 and SLC22A2 genes. They determined that both genes contain of 11 coding exons, with consensus GT/AG splice sites and conserved intron locations. The SLC22A3 gene is 77 kb, and the SLC22A2 gene is 45 kb.
Grundemann et al. (1998) mapped the SLC22A3 gene to 6q27 using FISH. By somatic cell hybrid analysis, Verhaagh et al. (1999) mapped the SLC22A3 gene to 6q26-q27. Using a BAC contig, Verhaagh et al. (1999) mapped the mouse Slc22a3 gene to chromosome 17 in a region showing homology of synteny with human 6q26-q27.
As the basis for association studies and candidate gene approaches, Lazar et al. (2003) investigated genetic variability of the SLC22A3 gene.
Grundemann, D., Schechinger, B., Rappold, G. A., Schomig, E. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nature Neurosci. 1: 349-351, 1998. [PubMed: 10196521] [Full Text: https://doi.org/10.1038/1557]
Grundemann, D., Schomig, E. Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. Hum. Genet. 106: 627-635, 2000. [PubMed: 10942111] [Full Text: https://doi.org/10.1007/s004390000309]
Lazar, A., Grundemann, D., Berkels, R., Taubert, D., Zimmermann, T., Schomig, E. Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). J. Hum. Genet. 48: 226-230, 2003. [PubMed: 12768439] [Full Text: https://doi.org/10.1007/s10038-003-0015-5]
Nagano, T., Mitchell, J. A., Sanz, L. A., Pauler, F. M., Ferguson-Smith, A. C., Feil, R., Fraser, P. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322: 1717-1720, 2008. [PubMed: 18988810] [Full Text: https://doi.org/10.1126/science.1163802]
Sleutels, F., Zwart, R., Barlow, D. P. The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415: 810-813, 2002. [PubMed: 11845212] [Full Text: https://doi.org/10.1038/415810a]
Verhaagh, S., Schweifer, N., Barlow, D. P., Zwart, R. Cloning of the mouse and human solute carrier 22a3 (Slc22a3/SLC22A3) identifies a conserved cluster of three organic cation transporters on mouse chromosome 17 and human 6q26-q27. Genomics 55: 209-218, 1999. [PubMed: 9933568] [Full Text: https://doi.org/10.1006/geno.1998.5639]
Wu, X., Kekuda, R., Huang, W., Fei, Y.-J., Leibach, F. H., Chen, J., Conway, S. J., Ganapathy, V. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake-2) and evidence for the expression of the transporter in the brain. J. Biol. Chem. 273: 32776-32786, 1998. [PubMed: 9830022] [Full Text: https://doi.org/10.1074/jbc.273.49.32776]