SLC41 Transporters—Molecular Identification and Functional Role

Abstract

The solute carrier family 41 (SLC41) encompasses three members A1, A2, and A3. Based on their distant homology to the bacterial Mg^2 + channel MgtE, all have been linked to Mg^2 + transport. There is only very limited knowledge on the molecular biology and exact functions of SLC41A2 and SLC41A3. SLC41A1 is ubiquitously expressed and data on its functional and molecular properties, regulation, complex-forming ability, and spectrum of binding partners are available. SLC41A1 was recently identified as being the Na⁺/Mg^2 + exchanger (NME)—a predominant Mg^2 + efflux system. Mg^2 +-dependent and hormonal regulation of NME activity is now known to depend on the intracellular N terminus of SLC41A1 that is involved in Mg^2 + sensing and contains phosphorylation sites for protein kinase (PK) A and PKC. Data showing a link between SLC41A1 and human disorders such as Parkinson's disease, nephronophthisis (induced by the null mutation c.698G>T in renal SLC41A1), and preeclampsia make the protein a candidate therapeutic target.

Introduction

Magnesium (Mg^2 +), in particular, its free intracellular form, plays an important role as a cofactor for many enzymes, as a modulator of ion channels, and in numerous other processes such as protein synthesis, nucleic acid stability, neuromuscular excitability, secretion of hormones, and in antagonizing the actions of Ca^2 + (Bara and Guiet-Bara, 2001, Garban, 1997, Hartwig, 2001, Jóna et al., 2001, Mooren et al., 2001; Watanabe & Dreyfus, 1972; White & Hartzell, 1989). Therefore, the regulation of extracellular and intracellular Mg^2 + levels by transmembrane and transepithelial transport processes is critical for numerous cellular and organ functions. At a functional level, the presence of such active plasma membrane Mg^2 + transport mechanisms has been indicated for a long time, but the identification of their molecular entities has started only recently (reviewed in Quamme, 2010).

Among Mg^2 + transporters are the three members A1, A2, and A3 of solute carrier family 41 (SLC41) with which this review deals. All of them are distantly homologous to the unique bacterial Mg^2 + transport protein MgtE (Smith, Thompson, & Maguire, 1995), suggesting that they also may be involved in transport of the ion across cell membranes (Quamme, 2010, Wabakken et al., 2003). Indeed, the group of Quamme (Goytain and Quamme, 2005a, Goytain and Quamme, 2005b, Quamme, 2010) demonstrated that all three SLC41 isoforms mediate electrogenic transport of Mg^2 + when cloned from renal mouse distal tubule cells and heterologously expressed in Xenopus laevis oocytes. Furthermore, in a Salmonella enterica strain (MM281) displaying disruption of all natural Mg^2 + transporters, overexpression of hSLC41A1 functionally substitutes these transporters and thereby restores bacterial growth (Kolisek et al., 2008).

Using a Mag-Fura2-based fluorescence spectroscopic assay on HEK293 cells overexpressing human SLC41A1, our group performed the first direct studies showing SLC41A1-linked Mg^2 + transport in a mammalian cell system (Kolisek et al., 2008, Kolisek et al., 2012). According to our data, SLC41A1 is a functional Mg^2 + carrier that normally mediates efflux of the ion (Kolisek et al., 2008) and functions as a Na⁺/Mg^2 + exchanger (NME). The NME is the best characterized Mg^2 + transporter of nonepithelial cells and tissues (Günther and Vormann, 1995, Hintz et al., 1999, Xu and Willis, 1994, Yoshimura et al., 1995). The NME was first described in chicken and turkey red blood cells by the laboratory of Günther (Günther and Vormann, 1985, Günther et al., 1984). This laboratory (Büttner et al., 1998, Günther and Vormann, 1990a) and others (Feray and Garay, 1986, Flatman and Smith, 1996, Xu and Willis, 1994) studied the Na⁺-dependent Mg^2 + transporter in numerous vertebrate erythrocytes. Over the years, NME activity has been identified in the majority of examined mammalian cell types (Cefaratti and Ruse, 2007, Fagan and Romani, 2001, Handy et al., 1996, He et al., 2005, Schweigel et al., 2006, Tessman and Romani, 1998).

Regulated Mg^2 + efflux by the NME is essential for the maintenance of free intracellular magnesium concentrations ([Mg^2 +]_i) at levels between 0.4 and 1.2 mM (Schweigel et al., 2006, Standley and Standley, 2002), and for Mg^2 + transport across intestinal, renal, placental, and mammary epithelia (Leonhard-Marek et al., 2005, Quamme, 1989, Shaw et al., 1991, Wolf et al., 2009). Additionally, hormones/mediators activate the NME to induce an [Mg^2 +]_i decrease, which directly or indirectly influences cellular transport mechanisms and physiological functions (Fagan and Romani, 2001, He et al., 2005, Kolisek, Sponder, et al., 2013). NME disruption or dysregulation may alter systemic and intracellular Mg^2 + homeostasis and participate in the pathogenesis of various diseases and associated events such as primary hypertension (Kisters, Krefting, Barenbrock, Spieker, & Rahn, 1999), ischemic heart disease (Altura & Altura, 1995), diabetes (Saris, Mervaala, Karppanen, Khawaja, & Lewenstam, 2000), cystic fibrosis (Vormann, 1992), neurodegeneration (Barbagallo et al., 2011, Lovitt et al., 2010), inflammation (Weglicki & Phillips, 1992), and preeclampsia/eclampsia (Weaver, 1986).

Although members A2 and A3 of the SLC41 family have also been linked to Mg^2 + transport, their molecular and biochemical properties (including membrane topology, cellular localization, transcriptomics, and proteomics) and physiology compared to SLC41A1 are only poorly explored. Therefore, this review concentrates on the molecular and functional characteristics of SLC41A1, in addition to its regulation and involvement in the pathophysiology of human diseases.