New molecular players facilitating Mg2+ reabsorption in the distal convoluted tubule

The renal distal convoluted tubule (DCT) has an essential role in maintaining systemic magnesium (Mg2+) concentration. The DCT is the final determinant of plasma Mg2+ levels, as the more distal nephron segments are largely impermeable to Mg2+. In the past decade, positional candidate strategies in families with inherited forms of hypomagnesemia have led to the identification of genes involved in Mg2+ handling. A large fraction of this resides in the DCT, namely, (i) the transient receptor potential channel melastatin subtype 6 (TRPM6), a divalent cation-permeable channel located at the luminal membrane of the DCT, facilitates Mg2+ entry from the pro-urine into the cell; (ii) the epidermal growth factor is a novel hormone regulating active Mg2+ transport through TRPM6; (iii) the voltage-gated K+ channel, Kv1.1, establishes a favorable luminal membrane potential for TRPM6-mediated Mg2+ transport; (iv) the Na+/K+-ATPase gamma-subunit (gamma-Na+/K+-ATPase) was identified as mutated protein in a family with isolated dominant hypomagnesemia. The molecular mechanism by which gamma-Na+/K+-ATPase is involved in DCT Mg2+ handling remains unknown; (v) a high percentage of patients with mutations in the renal transcription factor HNF1B (hepatocyte nuclear factor 1 homeobox B) gene develop hypomagnesemia; and (vi) Gitelman and EAST/SeSAME syndrome patients suffer from a similar tubulopathy due to mutations in NCC (NaCl cotransporter) and Kir4.1, respectively. In these patients, decreased expression of TRPM6 is proposed to cause hypomagnesemia. Insights into the molecular mechanisms of the identified genes, as well as the identification of novel genes, will further improve our knowledge about renal Mg2+ handling. Kidney International (2010) 77, 17-22; doi:10.1038/ki.2009.358; published online 7 October 2009