Regulation of magnesium balance: lessons learned from human genetic disease

Abstract

Magnesium (Mg(2+)) is the fourth most abundant cation in the body. Thus, magnesium homeostasis needs to be tightly regulated, and this is facilitated by intestinal absorption and renal excretion. Magnesium absorption is dependent on two concomitant pathways found in both in the intestine and the kidneys: passive paracellular transport via claudins facilitates bulk magnesium absorption, whereas active transcellular pathways mediate the fine-tuning of magnesium absorption. The identification of genes responsible for diseases associated with hypomagnesaemia resulted in the discovery of several magnesiotropic proteins. Claudins 16 and 19 form the tight junction pore necessary for mass magnesium transport. However, most of the causes of genetic hypomagnesaemia can be tracked down to transcellular magnesium transport in the distal convoluted tubule. Within the distal convoluted tubule, magnesium reabsorption is a tightly regulated process that determines the final urine magnesium concentration. Therefore, insufficient magnesium transport in the distal convoluted tubule owing to mutated magnesiotropic proteins inevitably leads to magnesium loss, which cannot be compensated for in downstream tubule segments. Better understanding of the molecular mechanism regulating magnesium reabsorption will give new opportunities for better therapies, perhaps including therapies for patients with chronic renal failure.

Keywords: TRPM6; human genetic disease; hypomagnesaemia; magnesium homeostasis.

Figures

Fig. 1.

Magnesium homeostasis. Panels represent the daily amount of Mg2+ intake and excretion. A daily net intake of ∼100 mg in the intestine results in a balanced 100 mg excretion in the kidney. In times of Mg2+ shortage, other tissues such as bone and muscle provide Mg2+ to restore blood Mg2+ levels. See also “Magnesium basics” in this supplement [5]. The conversion factor from milligrams to millimole is 0.04113.

Fig. 2.

A schematic overview of magnesium absorption pathways in the intestine, showing proteins associated with Mg2+ transport in enterocytes. In the intestinal epithelia, paracellular Mg2+ transport occurs via unidentified claudins, occuring concurrently with transcellular Mg2+ transport via transient receptor potential channel melastatin member 6 (TRPM6) and TRPM7 to facilitate Mg2+ absorption.

Fig. 3.

Magnesium reabsorption along the nephron. The glomerulus filters the blood and facilitates thereby the entrance of Mg2+ into the tubular system that subsequently mediates the reabsorption of 90–95% of Mg2+. Approximately 10–25% of Mg2+ is reabsorbed in the proximal tubule (PT). Bulk transport (50–70%) of Mg2+ is achieved along the thick ascending limb (TAL) of the loop of Henle. The final Mg2+ concentration in urine is determined in the distal convoluted tubule (DCT) where only 10% of Mg2+ is reabsorbed [28]. CNT, connecting tubule; CD, collecting duct.

Fig. 4.

Schematic overview of Mg2+ transport pathways in the thick ascending limb of the loop of Henle. The majority of Mg2+ is transported in this part of the nephron. Mg2+ absorption takes place in a paracellular fashion via claudins-16 and -19 of the tight junction complex. The driving force behind Mg2+ transport in the thick ascending limb is the transepithelial voltage gradient.

Fig. 5.

Ion transport pathways in the distal convoluted tubule. The final possibility of Mg2+ reabsorption is the tightly regulated transcellular transport in the distal convoluted tubule. In this schematic overview, all the proteins whose mutations cause hypomagnesaemia are shown. Mg2+ enters the cell via the TRPM6 Mg2+ channel that is regulated by EGF. The Kv1.1 K+ channel maintains transmembrane voltage that is the driving force for Mg2+ transport. The key molecule at the basolateral membrane is the Na+/K+-ATPase, whose expression is regulated by transcription factor HNF1B (not shown). The Na+/K+-ATPase activity is stimulated by its γ–subunit. Kir4.1 is responsible for recycling of K+ at the basolateral site of the cell. The basolateral Mg2+ transporter remains to be identified. Gitelman's-associated proteins NCC and ClC-Kb are responsible for Na+ and Cl− transport in the distal convoluted tubule.