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

Abstract

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 K0.5Na. 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.

Deletion of the transcription factor Prox-1 specifically in the renal distal convoluted tubule causes hypomagnesemia via reduced expression of TRPM6 and NCC

“…The DCT is also important for the control of renal magnesium (Mg 2+ ) excretion as the DCT is the sole site for active transcellular Mg 2+ reabsorption along the nephron. The Mg 2+ reabsorption in the DCT is mediated by the apical transient receptor potential cation channel subfamily M member 6 (TRPM6) [ 46 ] and modulated by the γ-subunit of the Na + -K + -ATPase encoded by the FXYD2 gene [ 2 , 27 ].…”

Tissue-resident, extravascular CD64-Ly6C-population forms a critical barrier for inflammation in the synovium

“…As expected, the MHCII + compartment exhibited elevated expression of genes associated with monocyte-derived DCs, including Cd209a, Cd74, and Nr4a3 (Boulet et al, 2019; Ponichtera et al, 2014; Stables et al, 2011) (Figure 2F and Supplemental Table 2C). The remaining non-DC MHCII - fraction was enriched for genes that are known to regulatory function in inflammation, lipid metabolism and angiogenesis including Crip2, Fxyd2, and Rnase4 (Cheung et al, 2011; Li et al, 2013; Mayan et al, 2018) (Figure 2G and Supplemental Table 2C). Thus, we conclude that the MHCII - compartment represents a pure population of tissue-resident synovial Ly6C - cells.…”

Clinical significance of P‑class pumps in cancer (Review)

“…Additionally, FXYD3 decreases K + affinity, spans the membrane twice instead of once, affects β subunit glycosylation and its specificity is low as it is also associated with the β subunit of HKA ( 41 , 42 ). The final locus of Na + reabsorption in the kidneys is from the collecting duct where FXYD4 (channel-inducing factor) is expressed as part of NKA, instead of FXYD2 ( 43 ). FXYD4 has a high affinity to Na + therefore ensuring that Na + is reabsorbed into the bloodstream ( 42 ).…”