Distribution and regulation of magnesium in the body fluids

This chapter is relevant to Section I3(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidates to "describe the function, distribution, regulation and physiological importance of sodium, chloride potassium, magnesium, calcium and phosphate ions". Magnesium the Sulfate has appeared three times in the past papers, but not Magnesium the Ion, which is sad because the pharmacology is boring but the physiology is fascinating. Question 19 from the first paper of 2012 was the only time this area was touched upon. The pass rate was only 20%, as it must have caught people off-guard. 

Jürgen Vormann's 2012 paper on magnesium is probably enough for anybody, or Ahmed & Mohammed (2019) - both are free and written with an excellent structure. Additionally, we should all be grateful to a reader (thank you Jane Durga) who pointed out the excellent paper by Schuchardt & Hahn (2017) that clarifies a lot of the factors influencing the absorption and regulation of magnesium.

Distribution of magnesium in the body fluids

The total body content of magnesium is approximately 15 mmol/kg. This means a 70kg male has about 1050 mmol, or about 25g of magnesium. Of this, 60% is locked up in bone. 39% is intracellular, and 1% is in the extracellular fluid. That means, the ECF contains only about 10mmol, at a concentration of approximately 0.7 mmol/L (though it can range up to 1.0).  Of the serum magnesium, about 40% is protein-bound (just like calcium), and some is complexed with phosphate lactate citrate, just like calcium, leaving about 55% as a free biologically active ion. In case people prefer a nice table of percentage body distributions, here's one from Vormann (2012).

Magnesium equilibrates freely across the extracellular fluid. There isn’t enough of it to matter seriously in any of the Gibbs-Donnan effects, or to contribute significantly to the various osmolar forces, but - if we were going to be nerdishly pedantic - we would have to admit that the Gibbs Donnan Factor for divalent cations is 0.90, which means if the plasma concentration of magnesium is 1.0 mmol/L, the interstitial fluid and lymph has only 0.9 mmol/L.

Intracellular magnesium

Intracellular magnesium is bound to ATP, cell wall lipids and many various enzymes, as those enzymes require magnesium to function. Additionally, magnesium, like calcium, binds to the phosphorylated groups of the cell wall lipids, and acts as a membrane stabilizer. The total concentration is therefore massive (perhaps in order of 20mmol/L) but the vast majority of this is not bioavailable. 

What is the intracellular concentration of free magnesium? This is difficult to estimate. Intracellular fluid is not a politely well-circumscribed pool of testable liquid, it is a ragged-edged mess of hydrated gel with little actual free water, to say nothing of free ions. Raftos et al (1999) measured a value of around 0.2-04 mmol/L in red cells, which is only slightly lower than plasma; Grubbs (2002) reported the findings of several other studies which got a range of 0.93 mmol/L for frog skeletal muscle, 0.72 mmol/L for guinea pig and 0.85 mmol/L for ferret ventricle, all the way up to 1.5mmol/L for some experiments. In short, something like 1.0 mmol/L should be a safe number to quote in a written exam answer, in the unlikely case that it ever comes up.

Regulation of magnesium intake

Only 30% of dietary magnesium ends up being absorbed, and of this amount, 90% is absorbed by passive paracellular mechanisms (Kerstan & Quamme, 2002). 

The rest is subject to saturable transcellular facilitated transport, mainly in the distal small bowel (jejunum and ileum). To oversimplify the excellent review by Schuchardt & Hahn (2017), the membrane transportert is TRPM6/7, and the basolateral extruder is CNNM4, a sodium/magnesium antiporter. TRPM6 is also the channel responsible for reabsorption of magnesium at the renal tubule, and seems to be regulated very tightly by intracellular magnesium, which means it relies on the work of the basolateral sodium/magnesium extruder (Voets et al, 2004) As long as the extruder keeps the intracellular magnesium concentration low, the apical channel will continue to sip magnesium ions from the intestinal lumen.  The hormonal regulation of this process remains elusive (it appears to be responsive to  increased intracellular cAMP and oestrogen, for example).  It does seem to respond to plasma levels, in the sense that patients or experimental animals with low plasma magnesium will retrieve a larger proportion of their dietary magnesium dose, whereas magnesium-replete organisms will leave it unabsorbed in their bowel.

Regulation of extracellular magnesium

Apart from oral intake and renal elimination, the amount of magnesium in the extracellular fluid can also be influenced by the exchange of magnesium into and out of the bone pool. This does not seem to be a fast or reliable mechanism of getting extra magnesium if you have a dietary deficiency (Maguire & Cowan, 2002). It may be regulated to some extent by PTH, as hypomagnesemia can cause both depressed PTH secretion and impaired tissue response to PTH.

Balance of intracellular and extracellular magnesium

Magnesium enters cells freely, without the need for active transport. But we still don’t know how. Doesn’t look like there is any sort of transporter. Changes in the ECF magnesium concentration result in a slow change of intracellular magnesium concentration, and the total magnesium content of intracellular fluid appears to be extremely tightly regulated, which suggests that there must be some control mechanism that keeps it in the cell, but nobody has ever found one. Efflux, certainly, seems to be mediated by a Na⁺/Mg²⁺ antiporter which extrudes magnesium in exchange for sodium, and this is what happens when the intracellular magnesium is for whatever reason increased. However, the reverse does not happen, i.e. intracellular magnesium does not appear to act as a ready exchange pool to replace extracellular losses. When Vormann et al fed their rats an extremely magnesium-poor diet, intracellular magnesium concentration remained essentially unchanged until the plasma levels fell to as low as 0.2 mmol/L  (Vormann et al, 1998). You'd be basically half dead of hypomagnesemia before the cells give up their stores.

Regulation of magnesium elimination

Magnesium is eliminated renally. 

• Free magnesium ions are ultrafiltered at the glomerulus
• 10–15% of the filtered magnesium is reabsorbed in the proximal tubule
• 60–70% is reabsorbed in the thick ascending limb of the loop of Henle
• 10-15% is reabsorbed in the distal convoluted tubule

Under normal circumstances urinary magnesium is highly conserved, i.e. only about 3% of the filtered magnesium ends up escaping in the urine (Ahmed & Mohammed, 2019). The first two mechanisms are fairly static in their proportional contribution, but the distal convoluted tubule mechanism is an active transport process that seems to be under the control of a divalent cation sensing receptor, which means it increases or decreases its activity according to plasma levels. Dai et al (2001) discuss this mechanism in great detail; to summarise for the impatient reader, the entire length of the nephron seems to express a calcium/magnesium sensitive receptor which resembles the one you find in the parathyroid gland, and it mediates all sorts of constructive reabsorption-antagonistic activity whenever it is bound to a divalent cation.

Physiological roles of magnesium

"Magnesium plays a vital role in over 300 reactions involving metabolism", "has several critically important roles in the body", or "essential for innumerous functions" is the kind of vague motherhood statement you usually see in the opening lines of a scientific paper about magnesium. Again, as with all "physiological role" descriptions, it seems pointless to call something out as "essential" or  "critically important", as the same could be said for any electrolyte;  the absence of anything would be disabling (just look at the effects of molybdenum deficiency). That "300 reactions" factoid comes from a 1981 paper by T.H. Gunther, and seems to be a randomly chosen number to describe the numerous enzymes which require magnesium as a co-factor.  In short, those opening sentences don't answer anything. If magnesium was called in to a performance review meeting, how would it justify its continuing position in the organisation?

The best answer to that question comes from an old paper by Michael F. Ryan (1991), which literally contains a table titled "physiological functions of magnesium". Here it is, essentially unchanged:

• Enzyme function:
  • Membrane-bound ATPases
  • Kinases, esp. creatine kinase
  • Alkaline phosphatase
  • Enolase
• Membrane function:
  • Cell adhesion
  • Transmembrane electrolyte movement (calcium and sodium)
• Structural function
  • Protein folding
  • Polyribosomes
  • Nucleic acids
  • Multienzyme complexes (eg. aldehyde dehydrogenase)
  • Mitochondria
  • Bone metabolism (affects the function of parathyroid hormone)
• Calcium antagonist
  • Muscle contraction/relaxation 
  • Neurotransmitter release (NMDA)
  • Action potential conduction
  • Vasodilation/relaxation of smooth muscle