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(Circulation Research. 2000;86:245.)
© 2000 American Heart Association, Inc.

Editorials

Mysteries of Magnesium Homeostasis

Elizabeth Murphy

From LMC, National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Correspondence to Elizabeth Murphy, Mail Drop D2-03, Box 12233, NIEHS, Research Triangle Park, NC 27709. E-mail murphy1{at}niehs.nih.gov

Key Words: heart • ß-adrenergic agonist • glucose transport • insulin • mitochondria

	Introduction

Top Introduction Is Intracellular Mg2+ Stable... Is Mg2+ Regulated by... Limitations of the Methods Unraveling the Mysteries References

 
In this issue of Circulation Research, Romani and colleagues¹ report that insulin stimulates uptake of ionized magnesium (Mg²⁺) into heart. This study is the latest in a series by Romani, Scarpa, and colleagues regarding hormone-regulated Mg²⁺ fluxes in heart and liver (References ¹ and ² and references therein). Over the past several decades, we have begun to uncover the mysteries of how cytosolic ionized calcium (Ca²⁺) is regulated and how it regulates cell function. However, the more abundant divalent cation Mg²⁺ still holds many secrets for us to unravel. Ca²⁺ signaling is facilitated by the large Ca²⁺ gradients (up to 10 000-fold) across the plasma and sarcoplasmic reticulum (SR) membranes. In contrast, only small gradients of Mg²⁺ (generally a factor of 2 or less) are reported across the plasma or intracellular membranes.^{3 4 5} In contrast to Ca²⁺ signaling, agonists do not cause large (order of magnitude) alterations in cytosolic Mg²⁺. Even upon hormonal stimulation, of heart and liver, which results in a 10% to 15% change in total cell magnesium, there is little or no change in cytosolic Mg²⁺. This lack of change in cytosolic Mg²⁺ has led many investigators to question whether Mg²⁺ is involved in hormone signaling.

	Is Intracellular Mg2+ Stable or Does It Function as an Intracellular Messenger?

Top Introduction Is Intracellular Mg2+ Stable... Is Mg2+ Regulated by... Limitations of the Methods Unraveling the Mysteries References

 
Cytosolic Mg²⁺, which is regulated by plasma membrane and organelle transport, and by intracellular binding, is maintained far from electrochemical equilibrium. If cytosolic Mg²⁺ were at electrochemical equilibrium, it would be 188 mmol/L, assuming a membrane potential of -70 mV and extracellular Mg²⁺ of 1 mmol/L. Because the plasma membrane is not impermeable to Mg²⁺, there must be transport mechanisms to extrude Mg²⁺ against its electrochemical gradient (for reviews, see References ^{6 7 8} ). However, Mg²⁺ permeability appears to be low and, therefore, Mg²⁺ transporters may not require a high V_max. Total cell magnesium would be in the range of 10 mmol/L if it were all free in the cytosol; however, as cytosolic Mg²⁺ levels are reported to be 0.5 to 1 mmol/L,^{3 9 10 11 12 13} 90% to 95% of the cell magnesium is bound or sequestered. Ionized Mg²⁺ levels in mitochondria are reported to be in the 0.5 to 1 mmol/L range,⁴ and Mg²⁺ levels in SR are reported to be 1 mmol/L⁵ ; therefore, most of the magnesium in the cell is bound, regardless of the precise location.

Numerous enzymes and transporters are regulated by Mg²⁺. For example, Mg²⁺ modulates Ca²⁺ release from the SR,¹⁴ alters the activity of many plasma membrane ion channels,^{15 16 17} , influences Bax-induced release of cytochrome c and apoptosis,¹⁸ and it has even been speculated that Mg²⁺ may bind to the transcription factor DREAM and alter transcription.¹⁹ In addition, most ATP in the cell is Mg²⁺ complexed and most ATPases use Mg-ATP. Thus, alterations in Mg²⁺ could have significant consequences for energy producing and utilizing enzymes. Although the large number of enzymes and transporters modulated by Mg²⁺ presents an opportunity for the cell to coordinately alter cell function, for example, in response to a hormonal signal, one can envision also that stable cell function is dependent on a stable level of cytosolic free Mg²⁺. One way of addressing this question is to examine whether cytosolic Mg²⁺ is altered by hormones or other agents.

	Is Mg2+ Regulated by Hormonal Signaling?

Top Introduction Is Intracellular Mg2+ Stable... Is Mg2+ Regulated by... Limitations of the Methods Unraveling the Mysteries References

 
There are a few reports suggesting small agonist-induced changes in cytosolic Mg^{2+10 12 20} ; however, many studies report no agonist-induced changes in cytosolic Mg2+.^{8 9 11} In contrast to the lack of support for ß-adrenergic agonist–induced change in cytosolic Mg²⁺,^{8 11} Romani et al¹ and Romani and Scarpa² and others^{21 22} have made the important observation that ß-adrenergic agonists stimulate a large Mg2+ efflux from perfused heart and isolated myocytes. Approximately 10% to 15% of the total cellular magnesium is lost from the cell over 5 minutes. Activation of the ß₂-adrenergic receptor has been shown to be primarily responsible for the stimulation of Mg²⁺ efflux.²³ Additional studies by Romani et al²⁴ have shown that carbachol addition to heart enhances Mg²⁺ uptake, leading to a 10% increase in total cell magnesium. These large changes in total cell magnesium occur with little or no change in cytosolic Mg²⁺,^{8 11} suggesting that the changes in total cell magnesium are due to changes in bound or sequestered magnesium. Furthermore, cytosolic Mg2+ is only 5% to 10% of the total cell magnesium, so the release of 10% to 15% of the total cell magnesium cannot be accounted for by a change in cytosolic Mg²⁺.

How can the cell mobilize 10% to 15% of the total cell magnesium within minutes without a measurable change in cytosolic Mg²⁺? It is clear that the change in total cell magnesium must be accompanied by a change in magnesium buffering in the cytosol or more likely in some organelle. There are two general scenarios by which ß-adrenergic agonists can lead to a 10% to 15% release of Mg²⁺. In the first scenario (altered buffering), the ß-adrenergic agonist alters magnesium buffering, causing a release of Mg²⁺, and the rate of release into the cytosol cannot exceed the maximum rate of efflux (V_max) across the plasma membrane. Thus, Mg²⁺ exits from the cell without leading to a measurable increase in cytosolic Mg²⁺. Because most magnesium in intracellular organelles appears to be bound rather than in the ionized form, it is likely that if ß-adrenergic agonists induce a release of Mg²⁺ from an organelle, that this release would be secondary to altered magnesium buffering in that organelle. In this first scenario, the change in magnesium buffering is the primary event caused by the hormone, which is responsible for the change in total cell magnesium. In the second scenario (altered transport), the ß-adrenergic agonist would increase plasma membrane Mg²⁺ efflux, which must lead to at least a slight decrease in cytosolic Mg²⁺, which must be quickly balanced by a release of Mg²⁺ from buffer sites or a release from intracellular organelles, which in turn must be due to a release from buffering sites. In the second scenario, the alteration in Mg²⁺ transport is primary and the magnesium buffering quickly compensates.

Data suggest that intracellular organelles are the primary pool for the increase and decrease in cellular magnesium content observed after hormonal stimulation. ß-Adrenergic agonists have been reported to cause an efflux of Mg²⁺ from mitochondria. Addition of cAMP to mitochondria causes an efflux of Mg²⁺ ,which is partially blocked by inhibitors of the adenine nucleotide translocator.²⁵ These data suggest that Mg²⁺ release from the mitochondria is the primary event leading to ß-agonist– or cAMP-stimulated Mg²⁺ efflux from the cell. There are also several reports suggesting that altered magnesium buffering, often in intracellular organelles, is important for regulating magnesium homeostasis. If magnesium buffering were altered, this would be expected to alter Mg²⁺, according to the following Equation: Mg²⁺=K_d[(Mg-ligand)/(uncomplexed ligand)].

Altered magnesium buffering could occur because of a change in ligand concentration per se (eg, a decrease in ATP). Also, the uncomplexed ligand available to Mg²⁺ is influenced by Ca²⁺, pH, and other ions that bind to the same sites as Mg²⁺. Because Mg²⁺ and Ca²⁺ bind to many common intracellular sites, a rise in Ca²⁺ would cause displacement of Mg²⁺ from mutual binding sites, thereby causing an increase in Mg²⁺. An alteration in Mg²⁺ in the cytosol or an organelle would be expected ultimately to alter transport at the plasma membrane. Romani et al²⁵ report that vasopressin stimulation of Mg²⁺ accumulation in liver cells, but not the ß-adrenergic stimulation of Mg²⁺ efflux, is attenuated by thapsigargin. Thapsigargin causes a decrease in endoplasmic reticulum calcium that would decrease calcium binding to mutual Ca²⁺/Mg²⁺ binding sites. This would increase uncomplexed ligand available to bind Mg²⁺ and lead to an increase in bound magnesium and a subsequent decrease in Mg²⁺ in the endoplasmic reticulum, which might be expected to enhance Mg²⁺ uptake into the endoplasmic reticulum. Tetanus and caffeine, which also produce a large decrease in SR calcium, have been shown by electron probe microanalysis to cause a 50% increase in magnesium in the SR.²⁶

The Mg²⁺ efflux measured after ß-adrenergic stimulation is dependent on the Na⁺ gradient across the plasma membrane. Romani et al²⁴ reported that decreasing extracellular Na⁺ or Ca²⁺ attenuates or blocks Mg²⁺ efflux. There are data to support Na⁺-dependent Mg²⁺ efflux in some cells (reviewed in Reference ⁶ ). However, there are conflicting data regarding the presence of an Na⁺-Mg²⁺ exchanger in myocytes.^{3 7 27 28 29} Murphy et al³ and Buri and McGuigan²⁷ showed a large increase in cytosolic Mg²⁺ when myocytes or isolated hearts were perfused with Na⁺-free buffer. However, when myocytes or hearts were perfused with a Na⁺-free, Ca²⁺-free buffer, the increase in cytosolic Mg²⁺ did not occur, and when myocytes or hearts were perfused with a Na⁺-free, Mg²⁺-free buffer, the increase in cytosolic Mg²⁺ was similar to that observed in Na⁺-free buffer. Thus, the increase in cytosolic Mg²⁺ observed in Na⁺-free buffer is dependent on extracellular Ca²⁺ but is not dependent on extracellular Mg²⁺. These data are consistent with the hypothesis that the rise in Mg²⁺ observed with Na⁺-free perfusion is not due to Na⁺-Mg²⁺ exchange but is due to Na⁺-Ca²⁺ exchange, which leads to an increase in total cell calcium, which binds to intracellular sites, which also can bind magnesium, thereby altering magnesium buffering (in the cytosol and/or intracellular organelles). This alteration in magnesium buffering secondarily leads to the increase in cytosolic Mg²⁺. Although these data suggest that with Na⁺-free and Ca²⁺-free perfusion there is not a large Mg²⁺ influx capable of altering cytosolic Mg²⁺ (Na_i/Mg_o), they do not rule out the presence of an exchanger that transports low levels of Mg²⁺, which does not cause a significant alteration in cytosolic Mg²⁺ (see Limitations). It is interesting that norepinephrine-induced Mg²⁺ efflux from the cell is blocked by removing extracellular Ca²⁺.²⁴ This would be consistent with a calcium-induced alteration in magnesium buffering as a factor in Mg²⁺ efflux. It is also interesting that the stimulation of Mg²⁺ efflux with ß-adrenergic agonists, as well as the stimulation of Mg²⁺ uptake with carbachol, is not dependent on extracellular Mg²⁺ over a wide range.²⁴ The carbachol-stimulated Mg²⁺ uptake is similar whether the extracellular Mg²⁺ is 2 µmol/L or 50 µmol/L or 1.2 mmol/L. This is most consistent with a role for magnesium buffering as the primary stimulus for the alteration in Mg²⁺ transport. However, it is extremely surprising that the Mg²⁺ uptake shows such a lack of dependence on extracellular Mg. This suggests an Mg²⁺ uptake transporter with a very low K_m.

Taken together, the data suggest that alterations in Mg²⁺ buffering are important for the hormonally induced changes in total cell magnesium. The observation that alterations in cell calcium (thapsigargin, Ca²⁺-free perfusion) alter Mg²⁺ uptake and efflux suggests that alterations in buffering are important. In addition, the lack of dependence of Mg²⁺ uptake or efflux on extracellular Mg²⁺ would again support a role for altered magnesium buffering as being a major stimulus for ß-adrenergic– and carbachol-induced altered cellular magnesium homeostasis. These data support a model in which alterations in magnesium buffering are the primary event driving altered magnesium homeostasis, although it is possible that hormonal stimulation could also alter Mg²⁺ transporters at either the plasma membrane or organelle membranes. It is worth noting that Mg²⁺ release from intracellular organelles is likely to be driven by alterations in magnesium buffering. Unlike Ca²⁺, there does not appear to be a significant Mg²⁺ gradient across the SR membrane⁵ ; thus, opening a release channel would not lead to a large flux of Mg²⁺. However, if magnesium buffering in the SR or another organelle were altered, this would be expected to lead to altered Mg²⁺ (see Equation), and the alteration in Mg²⁺ might be expected to alter cytosolic Mg²⁺ and ultimately to alter transport at the plasma membrane. However, these changes in cytosolic Mg²⁺ would likely occur more slowly than the changes in cytosolic Ca²⁺, which occur with release of SR calcium and thus would be less likely to cause a large measurable change in cytosolic Mg²⁺.

Romani et al¹ have added to the mysteries of magnesium with a report that insulin also stimulates Mg²⁺ accumulation in myocytes, but the intriguing new twist is that insulin-stimulated Mg²⁺ uptake is blocked if insulin-stimulated glucose transport is inhibited. It is possible that the increase in glucose transport and/or metabolism leads to altered magnesium buffering, and, therefore, if glucose transport is inhibited, Mg²⁺ uptake is inhibited. However, Romani et al¹ also report in studies using isolated myocytes that glucose transport is inhibited when extracellular Mg²⁺ is lowered below 25 µmol/L. It is possible that the inhibition of glucose transport upon removing extracellular Mg²⁺ is via a mechanism unrelated to the inhibition of Mg²⁺ uptake by the removal of glucose. For example, it could be that extracellular Mg²⁺ is necessary for the vesicle trafficking required for insulin stimulation of glucose transport by Glut4 translocation, whereas as discussed above, glucose transport could alter magnesium buffering and therefore be required for the insulin stimulation of Mg²⁺ uptake. However, it is also possible that the inhibition of glucose transport with low extracellular Mg²⁺ and the inhibition of Mg²⁺ uptake in the absence of glucose are mechanistically related. It is interesting that ß-adrenergic agonists, which also stimulate glucose uptake, enhance Mg²⁺ efflux, in contrast to insulin, which enhances Mg²⁺ uptake. Romani et al¹ suggest that this might be related to a difference in glucose transporters involved in the glucose uptake. Insulin stimulation of glucose transport is largely due to increased insertion of Glut4 into the plasma membrane. The mechanism responsible for ß-adrenergic–enhanced glucose uptake is less clearly understood but may involve stimulation of Glut1 rather than translocation of Glut4.

	Limitations of the Methods

Top Introduction Is Intracellular Mg2+ Stable... Is Mg2+ Regulated by... Limitations of the Methods Unraveling the Mysteries References

 
Measurements of Mg²⁺
Measurements of alterations in cytosolic Mg²⁺ are more challenging than measurements of alterations in cytosolic Ca²⁺ because although a 5- to 10-fold increase in cytosolic Ca²⁺ is common, such a large percentage change in cytosolic Mg²⁺ is unlikely because of the much higher basal cytosolic Mg²⁺. For example, a 1 µmol/L rise in cytosolic Ca²⁺ is easily measured against the 100 nmol/L basal cytosolic Ca²⁺, whereas a 1 µmol/L rise in cytosolic Mg²⁺ is lost in the 0.5 to 1 mmol/L basal cytosolic Mg²⁺. Because cytosolic Mg²⁺ is well buffered, it would require a very large flux to allow for a large percentage change in Mg²⁺. This may explain why only small changes in cytosolic Mg²⁺ are observed. However, even though the changes in cytosolic Mg²⁺ are small on a percentage basis, they may have physiologic consequences. Another limitation with measurement of cytosolic Mg²⁺ is the lack of selective indicators. Most studies use indicators based on APTRA,^{30 31} which are also sensitive to changes in ionized Ca²⁺. More Mg²⁺-selective indicators are critically needed for progress in this area.

Measurement of Mg²⁺ Fluxes
Most studies measuring Mg²⁺ flux use atomic absorption spectroscopy to quantify Mg²⁺ uptake and release into a perfusate (or extracellular medium) containing low (often nominally Mg²⁺ free) extracellular Mg²⁺. Because Mg²⁺ uptake and release are small, relative to the 1 mmol/L Mg²⁺ in a typical extracellular buffer, changes in extracellular Mg²⁺ would be lost in the large background of normal extracellular Mg²⁺. Atomic absorption spectroscopy measurements are also made of changes in total magnesium content in cells. However, if normal extracellular Mg²⁺ is present, it must be washed away before measurement of magnesium content of the cells. Often, measurements of total cell magnesium are made in cells or hearts perfused nominally Mg²⁺-free. Also, the changes in total cell magnesium are 10%, which are only 2 to 3 times higher than typical biological errors. Romani et al²⁴ have confirmed many of their results using ²⁸Mg isotope, but this isotope has very limited availability.

The finding of hormone-induced Mg²⁺ changes has not been observed by all investigators. Altschuld et al³² reported that they could not repeat the studies showing norepinephrine-induced release of Mg²⁺ from myocytes, nor did they detect a release of Mg²⁺ from mitochondria treated with cAMP. Using mag-fura-2, they found no change in mitochondrial Mg²⁺ on addition of cAMP. Also, they could not measure an increased uptake of Mg²⁺ into myocytes treated with carbachol. Altschuld et al³² did find that norepinephrine, in combination with low extracellular Mg²⁺, increased LDH release, which might account for the increase in Mg²⁺ efflux with norepinephrine. However, as noted by the authors, an increase in damaged cells would not account for the increased Mg²⁺ uptake observed with carbachol. The reasons for this discrepancy are unknown, but these conflicting results point out the importance of additional studies.

	Unraveling the Mysteries

Top Introduction Is Intracellular Mg2+ Stable... Is Mg2+ Regulated by... Limitations of the Methods Unraveling the Mysteries References

 
Future studies will be needed to determine whether the hormonally induced changes in total cell magnesium are important in agonist signaling and in regulating cell function. It is important to understand the physiological consequences of hormonally induced changes in magnesium homeostasis. What processes are regulated by these changes in total cell magnesium? An important related question for future research is determining whether these hormonally induced changes in total cell magnesium are accompanied by changes in Mg²⁺ in a cell compartment or organelle. The activities of enzymes and transporters are altered by changes in Mg²⁺ rather than total magnesium. The majority of data suggest that these hormonally induced changes in total cell magnesium are accompanied by little or no change in cytosolic Mg²⁺. However, it is likely that changes in magnesium buffering occur in intracellular organelles, and it is possible that changes in Mg²⁺ occur in these organelles. Measurement of Mg²⁺ in intracellular organelles is an important area for future research. This will require the development of more selective Mg²⁺ indicators. It is also important to develop strategies to localize Mg²⁺ selective indicators to intracellular organelles, as has been done for measurements of SR Ca²⁺.^{33 34}

Another area for future research is to explore the mechanisms responsible for the hormonally induced changes in Mg²⁺ transport and total magnesium content. Are changes in magnesium buffering primarily responsible for the altered magnesium homeostasis, or are there also changes in the activity of Mg²⁺ transporters? There is a paucity of information regarding the Mg²⁺ transporters. Lastly, although the data suggest that changes in buffering are important, we do not understand the mechanisms responsible for altered magnesium buffering.

In summary, the challenge for future research will be to elucidate whether agonist-induced alterations in Mg²⁺ fluxes lead to physiological alterations in function. Within the next few years, we should begin to unravel some of the mysteries of magnesium.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

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