SLC22A2 Membrane Protein Introduction

Introduction of SLC22A2

SLC22A2, also known as OCT2, organic cation transporter 2, or solute carrier family 22 (organic cation transporter) member 2, is a 62.5 kDa transmembrane protein that is composed of 555 amino acids. It contains 11 exons and in humans, encoded by the SLC22A2 gene mapped to the chromosome 6q25.3. SLC22A2 is a plasma integral membrane protein and belongs to the solute carrier (SLC) protein superfamily which comprises more than 300 members. It is primarily detectable in the kidney, located at the basolateral membrane of renal proximal tubules, also with some expression levels in the placenta, brain, skin, lung, spleen, and small intestine. This protein is a polyspecific transporter which can mediate the electrogenic transport of small organic cations.

Function of SLC22A2 Membrane Protein

The solute carrier superfamily 22 (SLC22), one of the broad-specificity transporters, is responsible for the distribution, absorption, and excretion of varieties of endogenous and exogenous substrates. This family contains the organic cation transporters, organic anion transporters, as well as the organic cation and zwitterion transporters. Of specific relevance to SLC22 is the member SLC22A2, a polyspecific organic cation transporter facilitating the transport of endogenous and exogenous cationic compounds including many drugs. There is one major physiological function of it being the removal of these substances from the circulation into epithelial cells of the kidney, after which they are excreted into the urine. Therefore, SLC22A2 is considered to play a critical role in the pharmacokinetic profile of cationic drugs. Clinically crucial drugs are transported by SLC22A2, such as lamivudine (antiretroviral), metformin (antidiabetic), and cimetidine (antihistamine). In addition, rs316019 has been identified as the most common variant of SLC22A2, with a frequency as high as 15% or more in large populations.

Fig.1 Metformin binding site in SLC22A2 protein. (Sajib, 2018)

Application of SLC22A2 Membrane Protein in Literature

1. Pearce B., et al. Effect of the African-specific promoter polymorphisms on the SLC22A2 gene expression levels. Drug Metab Pers Ther. 2018, 33(2): 85-89. PubMed ID: 29624501
   
   

   The data presented here indicated that African-specific promoter polymorphisms can cause a reduction of SLC22A2 gene expression levels in vitro, which in turn, was likely to influence the pharmacokinetic profile of cationic drugs.

2. Sandoval P.J., et al. Assessment of substrate dependent ligand interactions at the organic cation transporter OCT2 using six model substrates. Mol Pharmacol. 2018, 94(3):1057-1068. PubMed ID: 29884691
   
   

   Applying ASP model to a previously published screening study for the inhibition of OCT2-mediated ASP transport led to comparable statistics, with ~75% of 'active' inhibitors predicted correctly. The differential sensitivity of MPP transport to inhibition suggested that multiple ligands can simultaneously interact with OCT2 and supported that MPP was not used as a test substrate for OCT2 screening.

3. Xiao G., et al. Fampridine is a substrate and inhibitor of human OCT2, but not of human MATE1, or MATE2K. Pharm Res. 2018, 35(8): 159. PubMed ID: 29915999
   
   

   The results manifested that fampridine is a substrate and inhibitor of OCT2, but not MATE1 or MATE2K. And the active renal secretion of fampridine was mediated by human OCT2, but not MATE1 or MATE2K. As far as we know, fampridine was the first studied substrate specific to OCT2, but not to MATE1 or MATE2K.

4. Visentin M., et al. Fluorocholine transport mediated by the organic cation transporter 2 (OCT2, SLC22A2): implication for imaging of kidney tumors. Drug Metab Dispos. 2018, 46(8): 1129-1136. PubMed ID: 29794161
   
   

   The kinetic properties in this work suggested that OCT2 might play a pivotal role in [18F] fluorocholine uptake in vivo. OCT2-altered expression in primary cancer cells, in contrast with surrounding tissues, could be exploited in renal cell carcinoma (RCC) imaging, particularly to increase the detection sensitivity for small metastatic lesions.

5. Wilson N.C., et al. Organic cation transporter 2 (OCT2/SLC22A2) gene variation in the South African bantu-speaking population and functional promoter variants. OMICS. 2017, 21(3): 169-176. PubMed ID: 28253084
   
   

   Eleven polymorphisms were identified within the promoter and nine single-nucleotide polymorphisms (SNPs) within the SLC22A2 coding region. The data for SLC22A2 attested to the importance of considering genetic variations in various populations for drug response, safety, and global pharmacogenomics by different projects.

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Reference

1. Sajib A A, et al. (2018). Interaction of rs316019 variants of SLC22A2 with metformin and other drugs- an in silico analysis. JGEB.

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