SLC28A2 Membrane Protein Introduction

Introduction of SLC28A2

SLC28A2 is encoded by CNT2 or SLC28A2 gene and is also known as Sodium/nucleoside cotransporter 2, Concentrative nucleoside transporter 2 (CNT2), Na⁺/nucleoside cotransporter 2, Sodium-coupled nucleoside transporter 2, Sodium/purine nucleoside co-transporter (SPNT), Solute carrier family 28 member 2 (SLC28A2). It belongs to CNTs family, which is Na⁺-nucleoside cotransporters and are predicted to possess 14 TMDs, with an intracellular N-terminus and an extracellular C-terminus. CNT2 is responsible for transporting purine nucleosides and uridine and the region encompassing TMD 7-9 is responsible for substrate selectivity.

Function of SLC28A2 Membrane Protein

SLC28A2 (SLC28A2) is a Na⁺-coupled concentrative nucleoside cotransporter that preferentially translocates purine nucleosides across the plasma membrane. SLC28A2 mRNA is up-regulated during cell-cycle progression in synchronized proliferating cultured rat hepatoma Fao cells, and the amount of SLC28A2 protein is increased in regenerating rat liver soon after hepatectomy. Moreover, SLC28A2 is expressed in differentiated hepatocytes and its expression is lost in chemically induced hepatocarcinogenesis. Recent data regarding SLC28A2's properties point to a role beyond the mere salvage of extracellular nucleosides. A link between SLC28A2 function and energy metabolism has recently been provided by the demonstration that SLC28A2-mediated uptake of adenosine into IEC (intestinal epithelial cells)-6 activates AMPK (AMP-dependent protein kinase), thus promoting the phosphorylation of downstream targets such as acetyl CoA carboxylase-1. Moreover, SLC28A2-related transport activity is rapidly increased after A1R agonist activation in rat hepatocytes and hepatoma cells by a mechanism that requires functional KATP channels but does not seem to be associated with changes in SLC28A2 abundance at the plasma membrane.

Fig.1 Crystal structure of an NCT from Vibrio cholerae (Johnson, 2012).

Application of SLC28A2 Membrane Protein in Literature

1. Fernández-Veledo S., et al. Bile acids alter the subcellular localization of CNT2 (concentrative nucleoside cotransporter) and increase CNT2-related transport activity in liver parenchymal cells. Biochem. J. 2006, 395(Pt 2):337-344. PubMed ID: 16390326
   
   

   This article demonstrates that SLC28A2-related transport activity is regulated by intracellular transporter trafficking. This functional link between bile acids and SLC28A2 activity further indicates that this nucleoside transporter might have other physiological roles in addition to nucleoside salvage.

2. Owen R.P., et al. Molecular Determinants of Specificity for Synthetic Nucleoside Analogs in the Concentrative Nucleoside Transporter, CNT2. J. Biol. Chem. 2006, 281(36):26675-26682. PubMed ID: 16840788
   
   

   This article reveals that one residue in the C-terminal portion of SLC28A2 was found to significantly contribute to 2CdA selectivity: hSLC28A2-S354A, which cause an increase of 5-6-fold over hSLC28A2.

3. Medina-Pulido L., et al. Hypoxia and P1 receptor activation regulate the high-affinity concentrative adenosine transporter CNT2 in differentiated neuronal PC12 cells. Biochem. J. 2013, 454(3):437. PubMed ID: 23819782
   
   

   This article reports that SLC28A2 is likely to modulate extracellular adenosine and cell energy balance in neuronal tissue because SLC28A2 is downregulated in vitro and in vivo models of hypoxia/ischemia.

4. Huber-Ruano I., et al. Link between high-affinity adenosine concentrative nucleoside transporter-2 (CNT2) and energy metabolism in intestinal and liver parenchymal cells. Journal of Cellular Physiology. 2010, 225(2):620-630. PubMed ID: 20506327
   
   

   This article suggests that GRP58 appeared to be a negative effector of SLC28A2 function, whereas aldolase B flux modulated SLC28A2 activity via a mechanism involving acquisition of higher affinity for its substrates. These findings support the theory that SLC28A2 plays roles other than salvage and establishes links with energy metabolism.

5. Yee S.W., et al. Identification and Characterization of Proximal Promoter Polymorphisms in the Human Concentrative Nucleoside Transporter 2 (SLC28A2). The Journal of Pharmacology and Experimental Therapeutics. 2009, 328(3):699-707. PubMed ID: 19098160
   
   

   The data in this article indicate that the common variant, -146T>A, in the proximal promoter of SLC28A2 may result in an enhanced transcription rate of the gene and, thus, expression levels of SLC28A2. This SNP may play a role in variation in the pharmacokinetics and pharmacological effects of nucleoside analogs.

SLC28A2 Preparation Options

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Reference

1. Johnson ZL., et al. (2012) Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4 Å. Nature. 483(7390):489-493.

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