Magnesium Research (1993) 6, 2, 167-177
Summary: Magnesium plays an important role in a large number of cellular processes by acting as a cofactor in enzymatic reactions and transmembrane ion movements. Magnesium is a modulator of Na,K ion transport systems in numerous tissues. In this study, the interactions between magnesium and Na,K pathways are described. In the paracellular pathway, Na,K transports are generally increased by Mgo. In the cellular pathway, there are various processes: (1) Potassium channels - Mgi blocks the outward currents, first by interfering with the passage of K+ ions and inducing rectification of the channel current-voltage relationship, and secondly by completely blocking the channel pore and reducing the channel open probability; Mgo increases the K+ channel permeability in a leaky membrane. (2) Sodium channels Mgi blocks outward currents in a voltage- and dose-dependent manner, acts as a fast blocker by screening of surface charges, and produces an open channel block in several Na+ channels; Mgo increases Na+ transport in toad bladder and human amnion at high concentration by acting on the driving force of the sodium pump. (3) Na/K pump - Mgi and Mgo stimulate the Na/K exchange at low concentration and inhibit it at high concentration, by a stabilization of E2 forms of the enzyme which would reduce the rate of turnover of the pump. (4) Na-K-Cl cotransport increasing Mgo concentration stimulates this system in red cells and human amnion, and the bumetadine-sensitive K+ transport is sensitive to Mgi (5) KCl cotransport - The increase in Mgi inhibits this cotransport. (6) Na-H antiport - Na/H exchange responds to manipulations of cell magnesium but the effect is probably not a direct one; magnesium is required not for the transport process per se, but for the transduction of the volume stimulus (7) H-K pump - Mg activates this system. (8) Na-Ca antiport - The activity of this antiporter is inhibited by Mgo; the inhibition by magnesium is competitive with calcium. (9) Na-Mg exchange - in this system, the Na+ gradient provides the energy for net Mg2+-extrusion. In conclusion, intracellular and extracellular magnesium may be an important physiological regulator of the sodium and potassium pathways in the cell.
Key words: Cell membranes, extracellular magnesium, intracellular magnesium, pathways, potassium, sodium.
Magnesium, one of the most abundant intracellular divalent cations, plays an important role in a large number of cellular processes by regulating various biochemical reactions and acting as a cofactor in transmembrane movements 1. Magnesium has profound effects on solute and water transport in various cells, and intracellular Mg2 is known to interact with several channels. Excess Mg2 in the extracellular fluid is known, for example, to depress synaptic transmission and to cause rectification of the ionic channels coupled to N-methyl-D-aspartate receptor 2. When considering the transport systems, it is important to differentiate intracellular magnesium (Mgi) and extracellular magnesium (Mgo).
The action of magnesium depends on the cell membrane category. It is important to distinguish the tight cell membranes (presence of tight junctions) from the leaky cell membranes (presence of desmosomes and gap junctions). In cell membranes, ionic movements are carried out via two pathways: indeed, the paracellular pathway is hindered by the presence of tight junctions, ionic movements being first cellular and then paracellular. In a leaky cell membrane, the ionic movement may be either directly paracellular, or cellular, or cellular and paracellular (Fig 1).
In this review, the interactions between magnesium and the sodium and potassium pathways in cell membranes are examined. The most important pathways, observed by the use of inhibitors, are the following: paracellular Na (inhibited by triaminopyrimidinium) and K (protamines) pathways, cellular Na+ channels (chloride), cellular K+ channels (Ba2+) , Na/K-ATPase (ouabain), Na/H antiport (amiloride), K/Cl cotransport, NaK-Cl cotransport (bumetanide), K/H pump, Na/Ca antiporter, and the Na/Mg exchange (inhibited by quinidine and Mn) (Fig. 2).
There are various methods of studying the interactions between Mg and Na,K pathways.
(1) The patch-clamp method
Recordings of single channel currents 3 were performed using heat polished patch electrodes. The experiments utilized either the cell-attached 'open cell' recording configuration or excised 'inside-out'and'outside-out'membrane patches (in these cases the concentration of internal or external magnesium may be easily modified).
(2) The voltage-clamp method (recording of total channels)
There are several methods, particularly the classical oil gap voltage-clamp method 4 and the whole cell configuration of the patch-clamp techniques.
(3) Paracellular and cellular conductance measurements
Conductance measurements are achieved after implantation of two microelectrodes in the cell, passage of current, and recording the membrane potential 5.
(4) Isotopic measurements
Measurement of net and unidirectional isotopic sodium fluxes, for example during short-circuit conditions, were performed with 22Na and 24Na according to the method of Walser 6. In order to define the site of action of magnesium, experiments were conducted with a protocol in which the driving force of the sodium pump, as well as the conductances of the active transport pathway and the passive shunt pathway, were measured by the method of Siegel & Civan 7 in the presence and absence of magnesium in the mucosal solution,
(5) Use of Ionophores
Ionophores such as A23187 rapidly transport magnesium across the cell membrane and modify intracellular magnesium concentration.
The major part of the studies concerns the effects of extracellular magnesium. Extracellular Mg2+ blocks the passive movements of Na+ and K+ across the membrane of heart cells 8. An attractive explanation for the inhibition of transport is that Mg ions bind to and thus screen fixed negative charges on cell membranes. In the toad bladder, Mg increases the net sodium transport 9-10 but decreases it in rat renal proximal tubule and in jejunum.
In a leaky membrane (human amniotic membrane), there are various possibilities concerning the ionic transfer across the intercellular space (Figs. 3, 4): (1) a direct pathway across intercellular space, via desmosomes and gap junctions, the ionic mobility being a function of the size of the hydrated or dehydrated ion; (2) a passage in the intercellular space, then via the gap junction in the adjacent cell, this pathway being regulated by the electrical coupling between two adjacent cells; (3) a passage in the intercellular space, then via the surface charges in the adjacent cell, this pathway being a function of the distribution and organization of the surface charges of the bilayer unit. This organization implicates a biphasic effect of magnesium on sodium transport: at oral concentrations the transfer is decreased because of screening of the surface charges; at parenteral concentrations, it is increased because magnesium ions release the surface charges which become accessible to sodium ions 11-13.
Intracellular Mg2+ would be without effect on the passive influx (backleak) component 9.
The decrease of the Na+ channel conductance of the oocyte, at high potentials, can be explained by a blocking action of Mgi in a voltage- and dose-dependent manner. The reduction in Na+ conductance for outward currents is caused by Mg block. Pusch 14 showed that Mgi acts as a fast blocker rather than gradually decreasing current, e.g. by screening of surface charges. The screening of negative surface charges at the intracellular side of the membrane has been proposed as an alternative mechanism for the blocking effect of Mgi 15. In 1991, Lin et al. l6, studying cerebellar granule cells, proposed a model in which Na+ and Mg2+ competitively occupy the sodium channel. In this model, Na+ and Mg2+ have to bind to the sodium channel during their passage through the membrane. The blockade of sodium currents may be caused by magnesium occupying the sodium channel, which prevents the further binding of sodium (if the binding site for Mg2+ is one of binding sites for Na+ during its passage) or interferes with the normal accommodation of Na+ by sodium channels. Blockade of the sodium channel by Mgi may occur for two different reasons. The first possibility is related to the selectivity of sodium channels. Mgi enters the sodium channels and binds to an inside site during the membrane depolarization. Because of the selectivity of the pore (the permeability ratio of Mg2+ to Na+ through the sodium channel is less than 0.1 17), Mg2+ is not further permeable and is even re-extruded due to the small extracellular Na+ inward flux through the channel. The other possibility is that the strong binding force between Mg2+ and the binding site retards the release of Mg2+ from the channel. In fact, the dissociation constant value for Mg2+ binding within the sodium channel at zero membrane potential is 8.65 ± 1.51 mM, which is smaller than that for Nai (83.76 ± 7.60 mM). Most probably, these two possibilities may coexist and influence each other, which may lead to the entrance of Mg2+ into the channel several times during the depolarization, giving high frequency flickering at the single channel level and thus producing an apparently single conductance decrease.
The study of external divalent cations shows that the order of efficacy for the gating shift at a concentration of 5 mM (Ca > Ba > Sr > Mg) was similar, but not identical, to that for block (Ca > Mg > Sr > Ba). Thus, the binding sites for external divalent cations associated with the gating shift are probably somewhat different from those associated with block. This tends to argue against the possibility that occupancy of the divalent cation blocking site in the channel pore causes the depolarization gating shift 18. This suggests that a negative charge is normally exposed to the external side of the channel in the closed state and that when the channel opens, this group moves into the channel protein. In a leaky epithelium (human amniotic membrane), Mgo, (2 mM) increases the Na+ movement in the sodium channels. This is due to an interaction with the negative surface charges by a binding effects 19 (Fig. 5).
Inhibitory effects of intracellular Mg2+ have been reported for outward currents through several channels.
(1) Muscarinic K+ channel
Stimulation of the muscarinic acetylcholine receptor causes an increase in outward current by activating a class of K+ channel in cardiac cells, thereby slowing the pacemaker activity. Hory & Irisawa 20,21, studying guinea pig atrial cells, showed that depletion of internal Mg2+ increased outward muscarinic K+ currents but decreased inward currents, thereby reducing the inwardly rectifying property of the channels. Mgi acts as a 'fast' ionic blocker by plugging the open channel pore from the inside of the cell and prevents outward K+ passage 22, thereby exhibiting an inward rectifying property. Intracellular Mg2+. at physiological concentration, has a dual action on the muscarinic K+ channel: first, Mg2+ activates the channel in the presence of guanosine triphosphate (GTP) through GTP binding proteins (G proteins), and secondly, it blocks outward currents through the channel causing the inwardly rectifying properties.
(2) Inwardly rectifying K+ channel
The inwardly rectifying K+ channel provides the resting K conductance in a variety of cells. This channel acts as a valve or diode, permitting entry of K+ under hyperpolarization, but not its exit under depolarization. The channel conductance is ohmic and the well known inward rectification of the resting K conductance is caused by rapid closure of the channel accompanied by a voltage-dependent block by intracellular Mg2+ ions at physiological concentrations 23 24. The outward single channel currents through the inwardly rectifying K+ channel responsible for the resting conductance appeared after the intracellular side of the membrane was exposed to an artificial solution. The outward current is blocked by internal Mg2+ at physiological concentrations. The outward open channel was found to fluctuate between sublevels in the presence of Mg2+ at micromolar concentrations. Binomial distribution of occupancy at each current level suggests that the inwardly rectifying K+ channel is composed of three identical K+conducting subunits 25,27 which operate cooperatively to form a single channel, each of which is blocked by internal Mg2+ in a voltage-dependent manner 28.
(3) ATP-sensitive K+ channel
Potassium-selective single membrane channels, inhibited by adenosine triphosphate (ATP), applied to the internal surface of the cell membrane (K+ -ATP channels) have been described in cardiac and muscle cells 29,30 and in insulin-secreting cell 31.
The rectification of currents passing through the K+ -ATP channel resulted largely from the blockade of the outward movement of K+ ions through the channel pore by Mg2+ ions upon the internal surface 32,33, thereby resulting in a negative slope of the conductance at positive potentials.
(4) Ca2+-activated K+ channel
Internal Mg2+ reversibly decreases the K+ current in a concentration-dependent manner in the large conductance Ca2+-activated K+ channel in primary cultures of rat skeletal muscle 35. Mgi2+ and K+ appear to compete and the apparent competition may arise from the screening of negative charges at the inner surface of the channel protein. The blocking effects of Mg2+would be present under physiological concentrations of this ion.
There are many other K+ channels regulated by Mg2+ ions. For example, external modifications of the Mg2+concentration indicated that Mg2+ ions are activators of the K+ channels on the maternal and fetal sides of the human amniotic membrane 36 (Fig. 5).
Na/K-ATPase is a membrane-bound enzyme responsible for the active transport of K+ and Na+ across the plasma membrane which maintains the ionic gradients. It consists of two subunits, the catalytic subunit and the β subunit, which is a glycoprotein. During ion transport, the enzyme is believed to proceed through two major conformational states, El and E2, characterized by different affinity for K+ and Na+. Within the framework of the two conformational states, the enzyme passes through different substrates, in the formation of which divalent cations can play an important role either by binding to the protein sites or, indirectly, through interaction with phospholipids 37. Gupte et al. 38 suggested that Mg2+ interacts primarily with the polar headgroups of the phospholipid in purified Na/K-ATPase, inducing structural changes in the lipid vesicles. Amler et al. 39 showed that Mg2+, increased the order of the membrane phospholipids and this change can be closely related to the protein arrangement followed by the steady state anisotropy of Na/K-ATPase.
At low concentration, on various tissues, Mgo stimulates the Na/K-ATPase 10,19,40,41; this stimulation probably reflects the magnesium requirement for pump phosphorylation. An excess of Mg2+ 10,40 inhibits the Na/K-ATPase, probably because of the stabilization of E2 forms of the enzyme which reduce the rate of turnover of the pump.
In 1991, Robinson & Pratap 42 described the modes of inhibition of Na/K-ATPase by Mg2+. These authors distinguish four steps at which Mg2, as a product of the ATPase reaction, might interact as an inhibitor. These are as follows: (1) Mg2+ bound with the phosphorylated enzyme could be released immediately after dephosphorylation. Mg2+ should be an uncompetitive inhibitor of K+. With Mg2+ release immediately preceding MgATP binding, Mg2+must be a competitive inhibitor of MgATP. (2) An alternative, additional step for Mg2+ release and for Mg2+ binding as an inhibitor would be that which follows MgATP binding to (K, Mg)E2. (3) The third possibility is that Mg2+ dissociates from (K,Mg)E1 MgATP, and binds back as a product inhibitor. (4) The fourth possibility envisages Mg2+ release following K+ release from (K,Mg)E1 MgATP. In this way, Mg2+ might inhibit by competing directly with Na+ or K+ for their specific sites on the cytoplasmic surface of the enzyme. Thus Mg2+ could act by occupying the Na+ activating sites of the ATPase reactions, the K+ activating sites of the phosphatase reaction, and the monovalent cation sites that accelerate deocclusion.
The Na-K-Cl cotransport system moves sodium, potassium and chloride ions across the cell membrane. Movement is electroneutral: the number of chloride ions moved equals the sum of the number of sodium and potassium ions. In most cells, the ratio of ions moved is 1Na:1K:2Cl. This system is activated by cell shrinkage and is important in regulating cell volume and potassium content 43. In principle, the transporter can move ions in both directions across the cell membrane but there are some exceptions (for example, in human amniotic membrane the cotransporter is on the fetal side only, and in most red cells, thermodynamic constraints dictate that the direction of net transport is inwards 45).
Ellory et al 46 indicate that the influx and efflux of sodium and potassium across the human red cell membrane by the bumetanide-sensitive route are inhibited by increasing concentrations of Mg. This inhibitory effect of magnesium was not due to a small reduction in zeta potential since the much larger reduction in zeta potential produced by neuraminidase did not affect transport. In the human red cell, there is a high Mgi sensitivity of cotransport: depletion of Mgifree inhibited and an elevation of Mgi free increased the cotransport rate 47. In ferret red cells 48, an increase in internal or external concentrations of magnesium stimulates bumetanide-sensitive transport, but the system is about five times more sensitive to internal magnesium. In the human amniotic membrane, Mgo increases the Na-K-2CI cotransport 19 (Fig. 5). The finding that external Mg stimulates bumetanide-sensitive potassium uptake may indicate a specific interaction between Mgo and the transport system, possibly by means of a specific magnesium binding site.
K-Cl cotransport is the electroneutral movement of one K+ ion with one Cl- ion across the cell membrane 43. K-Cl cotransport is usually measured as the flux of K+ which depends on the presence of Cl-, but is resistant to inhibition by ouabain and bumetanide.
Removal of intracellular magnesium by inclusion of EDTA in the medium markedly stimulates K-Cl cotransport whereas increasing the concentration of Mgi inhibits it 49-51.
These experiments show that physiological changes in intracellular ionized magnesium concentration change the activity of K-Cl cotransport.
The plasma membranes of a wide variety of animal cells contain a carrier-mediated transport system that brings about the transmembrane exchange of Na+ for H+. Recent evidence suggests that the plasma Na-H exchanger plays a critical role in the regulation of intracellular pH, the regulation of cell volume, the transepithelial transport of Na+ and HCO3-, the initiation of cell growth and proliferation in response to activating stimuli and growth factors, and the metabolic responses to hormones 52.
The studies by Parker et al. 53 indicate that depleting dog red cells of Mgi prevents activation of Na-H exchange by cell shrinkage but has no effect on activation by acidification of the cytosol. Replacing cell magnesium restores the activation of Na-H exchange by cell shrinkage. The action of magnesium would appear to be exerted either on a hypothetical volume sensor or on the mechanism by which changes lead to modifications in transport. On the other hand. the increase in Mgo facilitates the Na-H exchange across the human amnion 19. A question arises as to whether magnesium is the transducer for cell volume changes.
By analogy, an Mg2+-H+ exchanger, located in the apical membrane of the epithelium in the distal colon and rumen, is fully consistent with the stimulatory effects of volatile fatty acids on magnesium absorption at these sites 54, 55.
Mg2+ in the cells of periosteum and endosteum activates the H+/K+ pump which is necessary to keep the average pH of bone extracellular fluid slightly higher than that of the other extracellular compartments in order to stabilize bone 56.
The Na+-Ca2+ antiporter is a membrane carrier in the plasma membrane of certain mammalian cells that translocates Na+ and Ca2+ in opposite directions. The antiporter is electrogenic and the Na:Ca2+ stoichiometry is 3:1 57.
Mg2+ was known to be a weak inhibitor (K1=5-8 mM) of the Na+-Ca2+ antiporter in cultured heart cells 58 and cardiac membrane vesicles 59. Moreover, Mg2+ inhibits the Na+-Ca2+ antiporter in smooth muscle 60. These studies indicate that the inhibition of antiporter activity by Mg2+ is due to competition between Mg2+ and Ca2+. From this observation and the fact that the potency depended on the closeness of the crystal ionic radius to that of Ca2+, it seems that the divalent cations interact with the divalent site of the antiporter called the A site. Two classes of cation binding sites may be distinguished: a divalent A site that binds a single Ca2+ ion or one or two Na+ ions; and a monovalent B site that binds the third Na+ ion involved in the antiporter. Because the inhibition by Mg2+ is competitive with Ca2+, it would seem that Mg2+ binds to the A site 61.
The Na+/Mg2+ system transport is not an Na+ pathway regulated by Mg2+. but a countertransport which permits the entry of Na+ to the cell and the extrusion of Mg2+. A major problem with this model is that it has been very difficult to identify the Na+ fluxes which must accompany Mg2+ movements. In human red cell, Feray & Garay 62 may have identified the Na+ flux by using imipramine, which not only blocks Mg2+ but also blocks a component of Na+ influx. Cells were treated with ouabain and bumetanide to prevent changes in the activities of the sodium pump or Na-K-Cl cotransport system (the major part of the sodium transport systems in these cells), obscuring Na+ influx through the antiport. These data suggest that three Na+ ions move into the cell in exchange for every Mg2+ ion. Experiments following simultaneous changes in Na+ and Mg2+ content indicate a stoichiometry of 2Na:lMg2+ in chicken red cells 63 and 1Na+: 1Mg2+ in rat red cells 64 and ferret red cells 65. In frog skeletal muscle, an Na+/Mg2+ exchange mechanism may be involved in maintaining low levels of internal Mg2+ concentration 66. In rat cardiomyocytes 67, there is an Na+-dependent amiloride-sensitive efflux. The transmembrane gradients for Mg2+ and Na+ are coupled and an Na+/Mg2+ exchange mechanism might be involved in the regulation of [Mg]i, using the energy stored in the transmembrane sodium gradient to remove Mg2+ ions against their electrochemical gradient from the cells in exchange for Na+ ions.
Magnesium may well be an important physiological regulator of transport systems, and defects in Mg2+ metabolism may be responsible for some modifications in transport and cotransport systems. Intracellular Mg2+ plays an essential role in protein synthesis and it is a key cofactor for hundreds of enzymes. Moreover, it also modulates numerous direct, co- and countertransport mechanisms. The interactions between Mg2+ and Na+,K+ pathways indicate that internal Mg2+ inhibits or blocks ionic channels and antiport and activates or inhibits Na/K-ATPase as a function of the concentration. Conversely, external Mg2+ generally has an activator effect (Fig. 6). Intracellular and extracellular Mg2+ appears to be an essential factor in the regulation of the transport of Na+ and K+ through the cell membranes.
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