The rise and fall of novel renal magnesium transporters

Body Mg²⁺ balance is finely regulated in the distal convoluted tubule (DCT), where a tight interplay among transcellular reabsorption, mitochondrial exchange, and basolateral extrusion takes place. In the last decades, several research groups have aimed to identify the molecular players in these processes. A multitude of proteins have been proposed to function as Mg²⁺ transporter in eukaryotes based on phylogenetic analysis, differential gene expression, and overexpression studies. However, functional evidence for many of these proteins is lacking. The aim of this review is, therefore, to critically reconsider all putative Mg²⁺ transporters and put their presumed function in context of the renal handling of Mg²⁺. Sufficient experimental evidence exists to acknowledge transient receptor potential melastatin (TRPM) 6 and TRPM7, solute carrier family 41 (SLC41) A1 and SLC41A3, and mitochondrial RNA splicing 2 (MRS2) as Mg²⁺ transporters. TRPM6/7 facilitate Mg²⁺ influx, SLC41A1 mediates Mg²⁺ extrusion, and MRS2 and SLC41A3 are implicated in mitochondrial Mg²⁺ homeostasis. These proteins are highly expressed in the DCT. The function of cyclin M (CNNM) proteins is still under debate. For the other proposed Mg²⁺ transporters including Mg²⁺ transporter subtype 1 (MagT1), nonimprinted in Prader-Willi/Angelman syndrome (NIPA), membrane Mg²⁺ transport (MMgT), Huntingtin-interacting protein 14 (HIP14), and ATP13A4, functional evidence is limited, or functions alternative to Mg²⁺ transport have been suggested. Additional characterization of their Mg²⁺ transport proficiency should be provided before further claims about their role as Mg²⁺ transporter can be made.