Molecular determinants of magnesium homeostasis: insights from human disease

Abstract

The past decade has witnessed multiple advances in our understanding of magnesium (Mg(2+)) homeostasis. The discovery that mutations in claudin-16/paracellin-1 or claudin-19 are responsible for familial hypomagnesemia with hypercalciuria and nephrocalcinosis provided insight into the molecular mechanisms governing paracellular transport of Mg(2+). Our understanding of the transcellular movement of Mg(2+) was similarly enhanced by the realization that defects in transient receptor potential melastatin 6 (TRPM6) cause hypomagnesemia with secondary hypocalcemia. This channel regulates the apical entry of Mg(2+) into epithelia. In so doing, TRPM6 alters whole-body Mg(2+) homeostasis by controlling urinary excretion. Consequently, investigation into the regulation of TRPM6 has increased. Acid-base status, 17beta estradiol, and the immunosuppressive agents FK506 and cyclosporine affect plasma Mg(2+) levels by altering TRPM6 expression. A mutation in epithelial growth factor is responsible for isolated autosomal recessive hypomagnesemia, and epithelial growth factor activates TRPM6. A defect in the gamma-subunit of the Na,K-ATPase causes isolated dominant hypomagnesemia by altering TRPM6 activity through a decrease in the driving force for apical Mg(2+) influx. We anticipate that the next decade will provide further detail into the control of the gatekeeper TRPM6 and, therefore, overall whole-body Mg(2+) balance.

Figure 1

Renal regulation of Mg²⁺ homeostasis. A total of 80% of Mg²⁺ is filtered at the glomeruli, 15% of which is absorbed proximally, 70% in the TAL, and 15% in the DCT, leaving 3 to 5% to be excreted in the urine. The TAL is the main site of passive paracellular reabsorption of Mg²⁺, a process mediated by claudin-16 and -19. This paracellular reabsorption depends on the active reabsorption of Na⁺, which is mediated by apical entry through sodium potassium chloride cotransporter (NKCC) and efflux via the Na⁺,K⁺-ATPase. Efflux of chloride (Cl⁻) occurs through CLCKb, and K⁺ is recycled back into the lumen via ROMK. The Ca²⁺-sensing receptor (CaSR) acts to inhibit this process and prevent both paracellular Ca²⁺ and Mg²⁺ reabsorption. In the DCT, luminal Mg²⁺ enters via TRPM6. The mediator of its efflux is unknown. Intracellular Mg²⁺ and RACK1 inhibit TRPM6. EGF, cleaved from the basolateral membrane, activates TRPM6, and its expression is increased by estradiol. EGFR, EGF receptor; PT, proximal tubule.