Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase.

This article examines the central role of Na,K-ATPase (α1β1FXYD2) 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-ATPase 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. FXYD2 (γ subunit) is a regulatory subunit that adapts functional properties of Na,K-ATPase to cellular requirements. Mutations in FXYD2 (G41R), and transcription factors (HNF-1B and PCBD1) that affect FXYD2 expression are associated with hypomagnesemia with hypermagnesuria. These mutations result in impaired interactions of FXYD2 with Na,K-ATPase. Renal Mg wasting implies that Na,K-ATPase is inhibited, but in vitro studies show that FXYD2 itself inhibits Na,K-ATPase activity, raising K Na. However, FXYD2 also stabilizes the protein by amplifying specific interactions with phosphatidylserine and cholesterol within the membrane. Renal Mg wasting associated with impaired Na,K-ATPase/FXYD2 interactions is explained simply by destabilization and inactivation of Na,K-ATPase. We consider also the role of the Na,K-ATPase in Mg (and Ca) handling in Gitelman syndrome and Familial hyperkalemia and hypertension (FHHt). Renal Mg handling serves as a convenient marker for Na,K-ATPase activity in DCT.