SLC13 family of Na⁺-coupled di- and tri-carboxylate/sulfate transporters

Abstract

The SLC13 family comprises five genes (SLC13A1, SLC13A2, SLC13A3, SLC13A4, and SLC13A5) encoding structurally related multi-spanning transporters (8–13 transmembrane domains) with orthologues found in prokaryotes and eukaryotes. Mammalian SLC13 members mediate the electrogenic Na⁺-coupled anion cotransport at the plasma membrane of epithelial cells (mainly kidney, small intestine, placenta and liver) or cells of the central nervous system. While the two SLC13 cotransporters NaS1 (SLC13A1) and NaS2 (SLC13A4) transport anions such sulfate, selenate and thiosulfate, the three other SLC13 members, NaDC1 (SLC13A2), NaCT (SLC13A5) and NaDC3 (SLC13A3), transport di- and tri-carboxylate Krebs cycle intermediates such as succinate, citrate and α-ketoglutarate. All these transporters play a variety of physiological and pathophysiological roles in the different organs. Thus, the purpose of this review is to summarize the roles of SLC13 members in human physiology and pathophysiology and what the therapeutic perspectives are. We have also described the most recent advances on the structure, expression, function and regulation of SLC13 transporters.

Introduction

In humans, the SLC13 family (Table 1) comprises five genes encoding structurally related proteins, with corresponding orthologues found in non-vertebrate (bacteria, yeast, nematode worm, plant, and fruit fly) and vertebrate species (from zebrafish to mammals). The general structure model for SLC13 isoforms is predicted to have a central core domain encompassing from eight to thirteen transmembrane α-helices flanked by an intracellular N-terminus and an extracellular C-terminus that contains putative consensus glycosylation sites. SLC13 members have ubiquitous tissue distribution with predominant expression in the kidney, small intestine, liver, placenta, and brain.

Except for some non-vertebrate orthologues that are Na⁺-independent or distributed in organelles, SLC13 transporters mediate Na⁺-coupled anion substrate movement across the plasma membrane of the cells and are electrogenic, generally with a Na⁺:substrate coupling ratio of 3:1. However, according to their anion substrate specificities, SLC13 members can be functionally separated into two distinct groups: the Na⁺-sulfate cotransporters (NaS) that transport mainly sulfate, selenate, and thiosulfate, and the Na⁺-di- and tri-carboxylate cotransporters (NaDC) that carry Krebs cycle intermediates such as succinate, citrate, and α-ketoglutarate. While the NaS group is represented by the SLC13A1 and SLC13A4 genes, which encode for the renal Na⁺-dependent inorganic sulfate transporter-1 NaS1 (also known as NaSi-1) and the sulfate transporter-1 NaS2 (also known as SUT-1), respectively, the NaDC group is represented by the SLC13A2, SLC13A3, and SLC13A5 genes encoding the apical Na⁺-dependent dicarboxylate transporter-1 NaDC1 (also known as NaC1 and SDCT1), the basolateral Na⁺-dependent dicarboxylate transporter-3 NaDC3 (also known as NaC3 and SDCT2), and the Na⁺-dependent citrate transporter NaCT (also known as NaC2), respectively. In a previous review, the gene family of the Na⁺-Carboxylate cotransporters was referred to as the NaC gene family (Markovich and Murer, 2004). However, this abbreviation is already used for the Na⁺ channels such as the epithelial Na⁺ channel eNaC and may be therefore confusing. Thus, in this review we propose to use the original names for the three Na⁺- di- and tricarboxylate cotransporters. Therefore, NaDC1, NaCT, and NaDC3 will be used for NaC1, NaC2, and NaC3, respectively.

Given that the cloning of the different non-vertebrate and vertebrate SLC13 orthologues and their functional and molecular properties have been quite extensively reviewed in the past (Pajor, 2000, Pajor, 2006, Markovich and Murer, 2004), and their physiological and pathophysiological functions and regulation have been rather neglected in these reviews (Markovich and Murer, 2004), the present report summarizes earlier findings as well as recently published information on the cloning, structure, expression, function and regulation of SLC13 isoforms, with special focus on the roles of SLC13 members in human physiology and pathophysiology, as well as therapeutic perspectives.