Magnesium (Mg) is the second most abundant mineral in the human body after calcium. Magnesium (Mg2+) is the fourth most abundant cation in the body and the second most common intracellular cation after potassium (K+).
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The magnesium homeostasis or balance inside the body is tightly regulated. Intestines and kidneys regulate the absorption and excretion of the mineral to maintain its balance within a narrow range.The consequences of altered regulation in Mg2+ homeostasis can be devastating to the body. Hypermagnesemia, excess magnesium in the blood serum, can cause many neurological and cardiovascular disorders. Similarly, hypomagnesemia, insufficient magnesium serum levels impairing the regulation of homeostasis, can affect the nervous and cardiovascular systems with different clinical manifestations.
Regulation of magnesium homeostasis in blood serum
Magnesium homeostasis is regulated by the intestinal absorption, renal excretion and bone turnover.Intestinal absorption and Mg2+ regulation
The daily requirement of magnesium is around 300 to 400 mg. Only 25 to 75% of the ingested magnesium is absorbed by the human body.The passive paracellular absorption takes place predominantly in small intestine. Mg2+ ions flow down to balance the concentration gradient between intestinal capillaries and the digested intestinal contents. In certain conducive conditions like the presence of absorbed Na+ and water, magnesium may also be absorbed by the colon in a passive manner.
Active transcellular transport of Mg2+ occurs only in colon. It is brought about by the transient receptor potential melastatin 6 (TRPM6) cation channel, which is the member of superfamily of transient receptor potential (TRP) channels. TRPM6 gene encodes a protein containing an ion channel domain and a protein kinase domain.
TRPM6 gene is crucial for magnesium homeostasis and has an important role in epithelial magnesium transport and in the active renal and intestinal magnesium absorption. Mutations in this gene impair Mg2+ absorption in the gut and are associated with hypomagnesemia 1 (HOMG1) with secondary hypocalcemia and calcinosis.
Renal excretion and Mg2+ regulation
Regulation of the total body magnesium rests with the kidney. Kidney tightly matches the intestinal absorption magnesium with its excretion. Of the total plasma Mg2+, nearly 80% is filtered in the glomeruli. Nearly 85% of the filtered Mg2+ is reabsorbed passively along the nephron by a paracellular mechanism.The proximal tubule reabsorbs 20% of the filtered Mg2+ and a two third is reabsorbed by the thick ascending limb of Henle (TAL). It is noteworthy that except for Mg2+ most of the other known ions are reabsorbed to a great extent in the proximal tubule. The distal convoluted tubule (DCT) reabsorbs 5 to 10% of the filtered Mg2+ by an active transcellular mechanism brought about by TRPM6 channel. The process in DCT ultimately regulates Mg2+ excretion. Normally 3-5% of the filtered Mg2+ is excreted.
Magnesium reservoir in bones
The skeleton stores more than 60% of Mg2+ and has a crucial role in the regulation of Mg2+ homeostasis and balance. Mg2+ is part of the hydroxyapatite crystalline structure of bone. Of the remaining balance of body magnesium, approximately 35% is distributed in the soft tissues. The blood serum with tight regulation of homeostasis contains less than 1% of magnesium. Only 50% of the blood magnesium is available as free Mg2+ ions for homeostasis regulation and the rest is bound to anions and proteins, especially albumin.The mineral is leached from the bone to buffer and regulate the homeostasis in case of drop in the mineral balance. The down regulation of bone material is brought about by the increases in both osteoclast number and activity. In the situation of plentiful Mg2+ in nutrition and up regulation of the mineral homeostasis in the serum, the formation of new bone tissue and active mineralization is brought about by the increases in both osteoblast number and activity.
Intracellular magnesium homeostasis
Magnesium regulates various cellular functions. Metabolic or hormonal stimuli can bring about major changes in the intracellular homeostasis of eukaryotic cells by way of major fluxes of ions in either direction across the cell membrane and the membranes of cellular organelles. Much of the intracellular Mg2+ is localized in cellular organelles such as, mitochondria, nucleus, endoplasmic reticulum and sarcoplasmic reticulum. It is bound to phospholipids, proteins, nucleic acids, chromatin and nucleotides. Only a fraction of the intracellular Magnesium is found free in the lumen of these vesicles.The intracellular magnesium homeostasis is dynamically maintained by a set of entry and exit processes differently regulated by endocrines and metabolic processes. The entry mechanism is brought about by TRPM6 and TRPM7 channels. The exit or extrusion of Mg2+ is by various processes brought about by ATP reactions or by hormones like catecholamine and glucagon.
Magnesium wasting disorders
Isolated autosomal recessive hypomagnesemia (IRH) is a Mg2+ wasting disease, caused due a mutation in the gene encoding epithelial growth factor (EGF) that is expressed in distal convoluted tubule (DCT) along with transient receptor potential melastatin 6 (TRPM6). In IRH the regulation of Mg2+ homeostasis is impaired.Gitelman syndrome is characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. It is the most common monogenic disorder resulting in Mg2+ wasting, characterized by renal salt loss. Patients with this disorder have a mutation in the thiazide-sensitive Na+/Cl− co-transporter (NCC).
The rare monogenic disorder hypomagnesemia with secondary hypocalcemia (HSH) is due to a failure of regulation in the active transcellular reabsorption of Mg2+ for homeostasis from both the intestine and the kidney. It is caused due to a mutation in the transient receptor potential melastatin 6 (TRPM6).
Isolated dominant hypomagnesemia is caused by a defect in γ-subunit of the Na,K-ATPase with altered TRPM6 activity. The familial hypomagnesemia with hypercalciuria and nephrocalcinosis is caused due to mutations in claudin-16/paracellin-1 or claudin-19 resulting in hampered regulation of magnesium homeostasis.
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References: 1.http://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional 2.Andrea M.P. Romani. CELLULAR MAGNESIUM HOMEOSTASIS. Arch Biochem Biophys. Aug 1, 2011; 512(1): 1–23. 3.R. Todd Alexander, Joost G. Hoenderop and René J. Bindel. Molecular Determinants of Magnesium Homeostasis: Insights from Human Disease. JASN August 2008 vol. 19 no. 8 1451-1458 |
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