Physiology Note - Magnesium Homeostasis

 

Dr. Prithwiraj Saha; MBBS, MD, DrNB ; 

Associate Consultant, Fortis Escorts Heart Institute Delhi 

Email-pitusri@gmail.com  

Phone-9830509648 

Magnesium Hemostasis- Inside story of a neglected gem 

 Introduction: 

Magnesium is the fourth most cation and the second most intracellular in the body. It has significant 

function in excitable tissues and also acts as cofactor in hundreds of enzymatic reaction. It  plays an 

important role in  DNA and protein synthesis, oxidative phosphorylation, neuromuscular excitability 

and regulation of parathyroid hormone (PTH) secretion. 

 Distribution of Magnesium 

Total magnesium content of body is around 25-30 grams(1000 mmol).This is much less than 

contribution of other ions such as Calcium and phosphorus. About 99 percent of total magnesium is 

present intracellularly and only 1 % is in the extracellular space. Intracelullar magnesium is stored 

predominantly in bone (2/3 rd or approx 65 % ) followed by muscle and soft tissues. Most of the 

plasma magnesium (60-65%) is free and rest is in bound form. Of the remaining 35% to 40% bound 

form ,  5% to 10% is complexed to anions such as phosphate, citrate, and sulphate , and 30% is 

bound to proteins (25% bound to albumin and  rest to globulin).For this a formula for correction of 

magnesium levels in patients with hypoalbuminemia has been suggested like calcium :  

                                    ΔMg (mmol/L) = 0.005 × Δ albumin (g/L). 

Intracellular magnesium is primarily localized in the nucleus, mitochondria, endoplasmic (or 

sarcoplasmic) reticulum, and cytosol. Most of the magnesium is bound to proteins and negatively 

charged molecules such as nucleotides (e.g., ATP, ADP) and nucleic acids (e.g., RNA, DNA). 

Approximately 80% of cytosolic magnesium is complexed with ATP, whereas only 1–5% exists as free 

ionized magnesium, with cytosolic concentrations of about 0.2–1.0 mmol/L. 

In adults, total serum magnesium ranges from 0.70 to 1.10 mmol/L, and ionized magnesium from 

0.54 to 0.67 mmol/L.The extensive binding of magnesium within both intracellular and extracellular 

compartments prevents the establishment of a substantial transcellular free magnesium gradient. 

Formula for any element is- 

                                            

                                                          Fig.1  Important Conversion table 

 Physiological role of magnesium (Fig- 2 and 3) 

Magnesium has many important roles in body physiology. Becaude of it’s positive charge  

magnesium is capable of cross-linking negatively charged components of the cell membrane 

resulting  in charge shielding of the (negatively charged) cell surface. This gives rise to a drop in the 

neuromuscular, muscular and cardiac excitability as well as convulsive seizure-inhibiting action in 

eclampsia by increasing the extracellular concentration of magnesium. It also inhibits the calcium

induced release and action of transmitters (epinephrine, norepinephrine, acetylcholine, 

prostaglandins, bradykinin, histamine, and serotonin). By this, magnesium can lead to 

tranquillization, stress blocking and diminution of neuromuscular, muscular,3asospasm and cardiac 

excitability. It plays a significant function in the bone physiology by regulating parathyroid hormone 

secretion and by its indirect effect on vitamin D metabolism.It acts as cofactor for many important 

reactions including energy energy extraction, utilization and maintainence of genome(replication, 

transcription, translation, and DNA repair).  

                                                            

                                                            Fig.2  Functions of Magnesium 

                                                                        

 Normal Hemostasis:  (Fig-4) 

Magnesium homeostasis refers to the regulation of magnesium levels in the body to maintain a 

stable concentration necessary for normal physiological function. It involves a balance between 

intake, absorption, distribution, and excretion. Gut and kidney are the two most important organ 

involved in this. The recommended dietary allowance (RDA) for magnesium is approximately 350

400 mg per day for adult males and 280–300 mg per day for females, increasing to about 355 mg per 

day during pregnancy and lactation. Roughly one-third of the ingested magnesium is absorbed, while 

fecal and urinary excretion account for about 260 mg and 100 mg per day respectively. 

                                                

 Gastrointestinal handling:   (Fig.5) 

•  Magnesium absorption occurs mainly in small intestine(distal jejunum and the ileum) 

with some absorption in the colon as well.Absorption in colon becomes important in the 

context of dietary restriction or compromised magnesium absorption in the small 

intestine.  

• Under normal dietary conditions in healthy individuals, approximately 30% to 50% of 

ingested magnesium is absorbed but can increase absorption to as high as 80%.When 

dietary intake is restricted, fractional absorption of magnesium may increase up to 80%. 

Conversely, it may be reduced to 20% on high magnesium diets. 

• Magnesium absorption takes place both through transcellular and paracellular pathway. 

Magnesium absorption varies along different segments of the gastrointestinal tract; in 

certain regions, it increases proportionally with higher Mg²⁺ intake (‘nonsaturable’), 

whereas in others, it reaches a maximal capacity (‘saturable’), with excess magnesium 

being excreted in the feces. In general terms, paracellular transport provides often 

nonsaturable absorption, while transcellular absorption is frequently saturable due to 

limitations of transporters.(Fig.5) 

• In small intenstine absorption takes place both via transcellular pathway and 

paracellular pathway,among which paracellular pathway predominates.(Fig.5) At low 

intraluminal concentrations, magnesium is predominantly absorbed via the transcellular 

pathway, involving active transport across epithelial cells into the bloodstream, whereas 

at higher concentrations, absorption increasingly occurs through the passive paracellular 

route. The rate of magnesium absorption across the intestinal epithelium is dependent 

on the transepithelial electrical voltage (which is normally about +5 mV, lumen positive 

with respect to blood) and the transepithelial concentration gradient. Claudins are small 

transmembrane proteins which are key components of the paracellular channel,while 

TRPM6/TRPM7 channels form path for transcellular absorption.In the colon and cecum, 

transcellular magnesium absorption occurs via apical entry through TRPM6 and TRPM7 

channels. TRPM6 expression is upregulated in response to high dietary magnesium 

intake. Interestingly, proton pump inhibitors (PPIs) also induce TRPM6 expression, 

possibly as a compensatory response to reduced transporter function. Basolateral 

extrusion of magnesium in the intestine is mediated by CNNM2, either independently or 

in cooperation with CNNM4.  

• Under steady-state conditions, approximately 2% of absorbed magnesium is secreted 

through pancreatic, biliary, and intestinal secretions. In renal failure, intestinal 

magnesium excretion increases as a compensatory mechanism. 

                                            

• Intestinal absorption is influenced by the presence of other dietary components, such as 

oxalate, phytate, and insoluble fiber, and high levels of minerals including zinc, iron, and 

calcium, all of which can negatively impact magnesium absorption. 

• Proton Pump Inhibitors increase the gastrointestinal transluminal pH. This affects the 

intraluminal solubility of magnesium, increases the transepithelial electrical resistance, and 

down-regulates the function of TRPM6. Important factors associated with the risk of 

hypomagnesemia with PPI use include prolonged duration of exposure, dose, concomitant 

diuretic use, and genetic variants in TRPM6. 

 Renal handling: (Fig.6) 

Kidney plays an important role in magnesium hemostasis. About 70 to 80 percent of serum 

magnesium is filtered in glomerulus, where as 96 % of te filtered magnesium is reabsorbed back in 

nephron. Under normal conditions only 3–5% of the filtered magnesium is excreted in the urine. 

Approximately 10–30 % of filtered magnesium is re-absorbed in the proximal convoluted tubules, 

while 65–70% and 5-15 % is passively re-absorbed in the thick ascending loop of Henle and distal 

convoluted tubule respectively. 

                                                      

 

Proximal Tubule: (Fig.7) 

Renal handling is surprisingly different in case of Magnesium. As in case of other cations 

(Na+,K+,Ca+2) almost two third is absorbed in Proximal convoluted tubule,only 10-30%  is absorbed 

here in case of magnesium. Mg2+ absorption in the PT is passive, paracellular and is mostly 

unregulated. Understanding of molecular mechanisms of Mg2+ absorption in the PT is very limited. 

Indirect evidence implicates a role for claudin-2 in magnesium transport in the proximal tubule. 

Claudin-10a  is responsible for Cl− absorption. The Cl− absorption eventually turns the charge in the 

lumen positive and so provides a driving force for paracellular Mg2+ absorption. In a Claudin-10a 

knockout mouse, Claudin-2 expression increased, permitting more paracellular Mg2+ absorption and 

resulting in hypermagnesemia. 

                                                        

Thick ascending loop of henle   (Fig.8) 

TAL accounts for major site for tubular reabsorption of magnesium, accounting for 50%-65% 

of the filtered load . It  occurs across the paracellular route and depends on a lumen-positive 

electrical potential difference.  

In the thick ascending limb of the loop of Henle, sodium, potassium, and chloride are 

reabsorbed through the electroneutral Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2). More than 80% 

of the potassium entering via NKCC2 is recycled into the tubular lumen through the apical 

potassium channel ROMK(as intracellular potassium content is very high). Basolateral 

sodium extrusion is mediated by Na⁺/K⁺-ATPase, which maintains the electrochemical 

gradient essential for NKCC2 activity. Chloride exits basolaterally through ClC-Ka and ClC-Kb 

channels, whose function depends on the accessory subunit Barttin. Potassium recycling via 

ROMK and the paracellular back-leak of sodium generate a lumen-positive transepithelial 

potential. Inactivating mutations in NKCC2, ROMK, ClC-Ka, ClC-Kb, or Barttin result in Bartter 

syndrome. 

The lumen-positive potential difference provides the driving force for passive reabsorption 

of sodium, calcium, and magnesium via the paracellular pathway. Calcium and magnesium 

mediate by a paracellular channel composed of claudin-16 and claudin-19. Mutations in the 

genes coding for claudin-16 and -19 impair TAL reabsorption of both calcium and 

magnesium, leading to familial hypomagnesaemia with hypercalciuria and nephrocalcinosis 

(FHHNC). 

                                        

 

The calcium-sensing receptor (CaSR) plays a key role in regulating divalent cation transport 

in the thick ascending limb (TAL). Physiological activation of CaSR by hypercalcemia suppresses 

transcellular sodium reabsorption and upregulates the inhibitory tight junction protein claudin-14, 

which interacts with claudin-16 and claudin-19 to reduce paracellular calcium and magnesium 

reabsorption.(Fig.8 and 9) Consequently, activating mutations in CaSR result in autosomal dominant 

hypocalcemia, often accompanied by hypomagnesemia and, in some cases, a Bartter-like 

phenotype. Parathyroid hormone (PTH) provides additional regulation in this segment by enhancing 

magnesium reabsorption. 

Paracellular sodium reabsorption in the medullary thick ascending limb (TAL) is mediated 

mainly by claudin-10b. Deletion or loss of claudin-10b impairs paracellular sodium permeability 

while simultaneously enhancing calcium and magnesium reabsorption, mostly due to compensatory 

upregulation of claudin-16 and claudin-19 expression. These accounts for the characteristic 

electrolyte abnormalities observed in individuals with CLDN10 mutations or HELIX syndrome 

(hypohidrosis, electrolyte imbalance, lacrimal dysfunction, ichthyosis, and xerostomia), which 

include renal sodium wasting, hypermagnesemia, and hypocalciuria. 

 Distal Convoluted Tubule 

The distal convoluted tubule (DCT) is responsible for reabsorbing approximately 10% of filtered 

magnesium. Magnesium transport in the DCT occurs via a transcellular pathway mediated by the 

heteromeric TRPM6/TRPM7 channel at the apical membrane. Due to the relatively small 

concentration gradient, apical magnesium absorption relies on a hyperpolarized luminal membrane 

potential as in case of the thick ascending limb (TAL). Outward potassium current, likely mediated by 

the Kv1.1 channel, is thought to establish this membrane potential, and mutations in KCNA1, which 

encodes Kv1.1, have been associated with hypomagnesemia. 

Active transcellular magnesium transport is powered by the sodium gradient generated by the 

basolateral Na⁺/K⁺-ATPase. Basolateral potassium recycling through the Kir4.1 channel, which forms 

heteromers with Kir5.1, is essential for maintaining this gradient. Kir4.1/Kir5.1 complexes also 

function as extracellular potassium sensors that regulate DCT sodium reabsorption via the thiazide

sensitive Na⁺-Cl⁻ cotransporter (NCC), through the WNK-SPAK kinase signaling pathway. . Increased 

plasma K+ concentration depolarizes cells in the proximal portion of the distal convoluted tubule 

(DCT1) through effects dependent on the K+ channel Kir4.1/5.1. The decrease in 

intracellularelectronegativity leads to an increased intracellular Cl− concentration that alters the 

WNK family of kinases and their regulatory proteins in such a way that Na+/Cl− cotransporter (NCC) 

activity is decreased. Magnesium reabsorption in the DCT is further regulated by epidermal growth 

factor (EGF), which enhances TRPM6 activity. 

CNNM2 is localized in the basolateral DCT and is responsible for transport of magnesium to blood. 

Mutations in this gene cause severe hypomagnesemia and seizures. The transporter SLC41A3 is also 

present and the observation that murine knockout of Slc41a3 results in hypomagnesemia. 

 

 

 

 

 

 

 

 

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