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).

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).

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).

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).

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).

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

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).

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).

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).