Renal Mg handling, FXYD 2 and the central role of the Na,K‐ ATP ase

This article examines the central role of Na,K‐ ATP ase ( α 1 β 1 FXYD 2) in renal Mg handling, especially in distal convoluted tubule ( DCT ), the segment responsible for final regulation of Mg balance. By considering effects of Na,K‐ ATP ase on intracellular Na and K concentrations, and driving forces for Mg transport, we propose a consistent rationale explaining basal Mg reabsorption in DCT and altered Mg reabsorption in some human diseases. FXYD 2 ( γ subunit) is a regulatory subunit that adapts functional properties of Na,K‐ ATP ase to cellular requirements. Mutations in FXYD 2 (G41R), and transcription factors ( HNF ‐1B and PCBD 1) that affect FXYD 2 expression are associated with hypomagnesemia with hypermagnesuria. These mutations result in impaired interactions of FXYD 2 with Na,K‐ ATP ase. Renal Mg wasting implies that Na,K‐ ATP ase is inhibited, but in vitro studies show that FXYD 2 itself inhibits Na,K‐ ATP ase activity, raising K 0.5 Na. However, FXYD 2 also stabilizes the protein by amplifying specific interactions with phosphatidylserine and cholesterol within the membrane. Renal Mg wasting associated with impaired Na,K‐ ATP ase/ FXYD 2 interactions is explained simply by destabilization and inactivation of Na,K‐ ATP ase. We consider also the role of the Na,K‐ ATP ase in Mg (and Ca) handling in Gitelman syndrome and Familial hyperkalemia and hypertension ( FHH t). Renal Mg handling serves as a convenient marker for Na,K‐ ATP ase activity in DCT .