Chapter Seven - Sodium-Sulfate/Carboxylate Cotransporters (SLC13)

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Abstract

The SLC13 gene family is comprised of five sequence related proteins that are found in animals, plants, yeast and bacteria. Proteins encoded by the SLC13 genes are divided into the following two groups of transporters with distinct anion specificities: the Na+-sulfate (NaS) cotransporters and the Na+-carboxylate (NaC) cotransporters. Members of this gene family (in ascending order) are: SLC13A1 (NaS1), SLC13A2 (NaC1), SLC13A3 (NaC3), SLC13A4 (NaS2) and SLC13A5 (NaC2). SLC13 proteins encode plasma membrane polypeptides with 8–13 putative transmembrane domains, and are expressed in a variety of tissues. They are all Na+-coupled symporters with strong cation preference for Na+, and insensitive to the stilbene 4, 4’-diisothiocyanatostilbene-2, 2’-disulphonic acid (DIDS). Their Na+:anion coupling ratio is 3:1, indicative of electrogenic properties. They have a substrate preference for divalent anions, which include tetra-oxyanions for the NaS cotransporters or Krebs cycle intermediates (including mono-, di- and tricarboxylates) for the NaC cotransporters. This review will describe the molecular and cellular mechanisms underlying the biochemical, physiological and structural properties of the SLC13 gene family.

Introduction

The SLC13 gene family is comprised of structurally related membrane transport proteins with unique substrate specificities (Markovich, 2001; Markovich & Murer, 2004). They can be divided into the following two distinct groups: the Na+-sulfate (NaS) cotransporters and the Na+-carboxylate (NaC) cotransporters (Table 1). This review will focus on the functional mechanisms of the SLC13 transporters, including ion-coupling patterns, substrate specificities, regulatory domains, tissue distributions/expression patterns, physiological/pathological roles, as well as biochemical and structural information. The focus of this review will be on the vertebrate members of this family, with greatest emphasis on mammalian transporters, and will only briefly mention nonvertebrate, lower eukaryotic or prokaryotic SLC13 (gene-like) members. The review is divided into the following sections: the first part will discuss general features common to all vertebrate members of this gene family; the second part will focus on the NaS cotransporters (SLC13A1 and SLC13A4); the third part is devoted to the NaC cotransporters (SLC13A2, SLC13A3 and SLC13A5). Finally, future perspectives for these transporters will be discussed at the end of this review.

Section snippets

Discovery and Vertebrate Orthologs

Prior to the genome sequencing era when DNA sequence information was unavailable, the first several complementary Deoxyribo Nuclic Acids (cDNAs) encoding SLC13 gene members were isolated by expression cloning using Xenopus laevis oocytes (Markovich, 2008; Markovich, Werner, & Murer, 1999). The first cDNA to be cloned was Slc13a1, which encoded a rat NaS cotransporter [rNaS1 (Markovich, Forgo, Stange, Biber, & Murer, 1993)], followed by Slc13a2, a rabbit Na+-dicarboxylate cotransporter [rbNaC1 (

Members and Tissue Specificities

The three most studied mammalian NaS1 (SLC13A1) orthologs are human NaS1 [hNaS1 (Lee et al., 2000)], rat NaS1 [rNaS1 (Markovich et al., 1993)] and mouse NaS1 [mNaS1 (Beck & Markovich, 2000)]. hNaS1 was shown to be expressed in the kidney, rNaS1 mRNA was detected in kidney and small intestine (Markovich et al., 1993) and mNaS1 was strongly detected in kidney, ileum, duodenum/jejunum and colon, with weaker signals in cecum, testis, adrenal and adipose tissue.

The three most studied mammalian NaS2

Members and Tissue Specificities

The five major vertebrate NaC1 (SLC13A2) orthologs mostly studied are human NaC1 (Pajor, 1996), rabbit NaC1 (Pajor, 1995), mouse NaC1 (Pajor & Sun, 2000), rat NaC1 (Chen et al., 1998; Khatri et al., 1996; Sekine et al., 1998), and Xenopus NaC1 (Bai & Pajor, 1997). Northern blotting detected hNaC1 mRNA in kidney and intestine (Pajor, 1996); rbNaC1 mRNA was strongly expressed in kidney and jejunum, with weaker signals in liver (Pajor, 1995). Northern blotting detected mNaC1 mRNA in kidney and

Future Perspectives

Since the initial cloning of the SLC13 gene family members from the early 1990s, a significant amount of research has been undertaken on this transporter gene superfamily. NaC transporters most likely play an important role in the excretion of organic anions and small therapeutic drugs, including gluconate, sulfate and cysteine conjugates, thus making them excellent tools for therapeutic targets (Pajor, 1999b, 2006). Organic anions and small therapeutic drugs are excreted from hepatocytes into

Acknowledgments

Research in the authors’ laboratory has been supported by the National Health and Medical Research Council, Cancer Council Queensland and the Australian Research Council.

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