Magnesium biology

Abstract

Magnesium (Mg2+) is essential for energy metabolism, muscle contraction and neurotransmission. As part of the Mg-ATP complex, it is involved in over 600 enzymatic reactions. Serum Mg2+ levels are tightly regulated between 0.7 and 1.1 mmol/L by interplay of intestinal absorption and renal excretion. In the small intestine, Mg2+ is absorbed paracellularly via claudin-2 and -12. In the colon, transcellular absorption of Mg2+ is facilitated by TRPM6/7 and CNNM4. In the kidney, the proximal tubule reabsorbs only 20% of the filtered Mg2+. The majority of the filtered Mg2+ is reabsorbed in the thick ascending limb, where the lumen-positive transepithelial voltage drives paracellular transport via claudin-16/-19. Fine-tuning of Mg2+ reabsorption is achieved in the distal convoluted tubule (DCT). Here, TRPM6/7 tetramers facilitate apical Mg2+ uptake, which is hormonally regulated by insulin and epidermal growth factor. Basolateral Mg2+ extrusion is Na+ dependent and achieved by CNNM2 and/or SLC41A3. Hypomagnesemia (serum Mg2+ <0.7 mmol/L) develops when intestinal and/or renal Mg2+ (re)absorption is disturbed. Common causes include alcoholism, type 2 diabetes mellitus and the use of pharmacological drugs, such as proton-pump inhibitors, calcineurin inhibitors and thiazide diuretics. Over the last decade, research on rare genetic and acquired Mg2+ disorders have identified Mg2+ channel and transporter activity, DCT length, mitochondrial function and autoimmunity as mechanisms explaining hypomagnesemia. Classically, treatment of hypomagnesemia depended on oral or intravenous Mg2+ supplementation. Recently, prebiotic dietary fibers and sodium-glucose cotransporter 2 inhibitors have been proposed as promising new therapeutic pathways to treat hypomagnesemia.

Keywords: SGLT2 inhibitors; drug-induced hypomagnesemia; hypomagnesemia; magnesium homeostasis; magnesium pathophysiology.

Figure 1:

Intestinal magnesium uptake. Intestinal absorption in the small intestines is mainly driven by paracellular transport facilitated by claudin-2, -7 and -12. Luminal Mg concentrations are linearly correlated to Mg²⁺ uptake, making the former the driving force of Mg²⁺ uptake. In the caecum and colon magnesium is absorbed via the transcellular pathway. Apically, TRPM6/7 is responsible for magnesium influx while CNNM4 as potential sodium–magnesium exchanger facilitates magnesium efflux on the basolateral side. CNNM4 = Cyclin M4; TRPM6/7 = Transient receptor potential family member 6 and 7 heterotetradimers.

Figure 2:

Renal magnesium regulation. Claudin -2 and -12 are thought to be the main key players driving magnesium reabsorption in the PT facilitated by a slightly lumen negative transepithelial voltage. In the TAL, NKCC2 and ROMK are responsible for maintaining a lumen positive transepithelial voltage, mainly through the back leak of potassium into the luminal space. Claudin-14, -16 and -19 are responsible for magnesium reabsorption by paracellular transport. RRAGD activated mTorc1 which is thought to influence NKCC2 and Claudins-14, -16 and -19 leading to increased magnesium uptake. Basolaterally, Na-K-ATPase, Kir4.1/Kir5.1, ClC-Kb and CaSR are responsible to maintain intracellular sodium, potassium and chloride levels in balance. CaSR can be activated by calcium leading to inhibition of ROMK and increased claudin-14 expression, ultimately leading to a change in the transepithelial voltage. In the DCT, magnesium influx is facilitated by the TRPM6/7 channel. TRPM6 is regulated by PTH, insulin, EGF and estrogen. NCC is responsible for sodium and chloride influx. ClC-Kb, Kir4.1/Kir5.1 Na-K-ATPase and CNNM2/SLC41A3 are located on the basolateral side. The role of CNNM2 in magnesium homeostasis is heavily discussed, however it has been suggested that CNNM2 acts as a sodium–magnesium exchanger. Since the debate has not been settled yet, potential other sodium–magnesium exchangers haven been explored further, one being SLC41A3. CaSR = Ca²⁺ sensing receptor; CNNM2 = Cyclin M2; ClC-Kb = voltage-gated Cl^– channel Kb; EGF-R = EGF receptor; ER = estrogen receptor; Ins-R = insulin receptor; Kir = inward rectifier-type K⁺ channel; NCC = Na⁺-K⁺ cotransporter; NKCC2 = Na⁺-K⁺-2Cl- cotransporter; PTH-R = PTH receptor; ROMK = renal outer medullary K⁺ channel; TRPM6/7 = Transient receptor potential family member 6 and 7 heterotetradimers.

Figure 3:

Mechanisms of drug-induced-hypomagnesemia and autoimmunity Claudin-16 autoantibodies are directed against Claudin-16 resulting in misfunction and decreased magnesium reabsorption in the TAL. Loop diuretics act in the TAL by inhibition of NKCC2 resulting in a disturbance of the transepithelial membrane potential resulting in disruption on magnesium reabsorption. The opposing process is thought to take place during the use of SGLT2 inhibitors. Increased sodium levels in the preurine lead to overactivation of NKCC2 resulting in an increased transepithelial membrane potential driving magnesium reabsorption. Thiazide diuretics block NCC in the DCT leading to decreased sodium levels resulting in inhibition of TRPM6/7. Calcineurin inhibitors lead to decreased expression of TRPM6 resulting in reduced Mg²⁺ uptake in the DCT. CaSR = Ca²⁺ sensing receptor; CNNM2 = Cyclin M2; ClC-Kb = voltage-gated Cl^– channel; EGF-R = EGF receptor; ER = estrogen receptor; Ins-R = insulin receptor; Kir = inward rectifier-type K⁺ channel; NCC = Na⁺-K⁺ cotransporter; NKCC2 = Na⁺-K⁺-2Cl^– cotransporter; PTH-R = PTH receptor; ROMK = renal outer medullary K⁺ channel; TRPM6/7 = Transient receptor potential family member 6 and 7 heterotetradimers; SGLT2 = sodium-glucose cotransporter 2.