Mg is involved in more than 300 essential metabolic reactions (7). The Mg ion (Mg²⁺) forms complexes with a variety of organic molecules. Mg²⁺ is essential for many enzymatic reactions and has two general interactions: (a) Mg²⁺ binds to the substrate, thereby forming a complex with which the enzyme interacts, as in the reaction of kinases with Mg adenosine triphosphate (MgATP); and (b) Mg²⁺ binds directly to the enzyme and alters its structure or serves a catalytic role (e.g., exonuclease, topoisomerase, and RNA and DNA polymerases) (6, 8, 9). Overall, the predominant action of Mg is related to ATP utilization. ATP has a strategic position in “freeenergy” currency for virtually all cellular processes, by providing high-energy phosphate. It exists in all cells,
primarily as MgATP^2-. Mg therefore is essential for the function of the glycolytic cycle, citric acid cycle, protein kinases, RNA and DNA polymerases, lipid metabolism, and amino acid activation, as well as playing a critical role in the cyclic adenosine monophosphate (cAMP) and phospholipase C second-messenger systems (5, 6, 10, 11, 12).

Another important role of Mg is its ability to form complexes with nucleic acids. The negatively charged ribose phosphate structure of nucleic acids has a high affinity for Mg²⁺; the resulting stabilization of numerous ribonucleotides and deoxyribonucleotides induces important physicochemical changes that affect DNA maintenance, duplication, and transcription. (6, 7, 8, 9, 13). In addition, the binding of hydrated Mg²⁺ by transfer RNA (tRNA) and modified tRNA and its DNA analogs results in structures that cannot be duplicated by the binding of other metals (6, 7, 8, 9, 13).

Mg, calcium (Ca²⁺), and some other cations react with hydrophilic polyanionic carboxylates and phosphates of the various membrane components to stabilize the membrane and thereby affect fluidity and permeability. This process influences ion channels, transporters, and signal transducers (6).

Ion channels constitute a class of proteins across the cell membrane, which allow passage of ions into or out of cells when the channels are open. Ion channels are classified according to the type of ion they allow to pass, such as sodium (Na⁺), potassium (K⁺), or Ca²⁺ (14). Mg²⁺ plays an important role in the function of certain ion channels. A deficit of Mg results in cellular potassium (K) depletion (14). Mg²⁺ is necessary for the active transport of K⁺ out of cells by Na⁺/K⁺-ATPase (15). Another mechanism for K⁺ loss is an increased efflux of K⁺ from cells via other Mg²⁺-sensitive K⁺ channels, as has been seen in skeletal and heart muscle (16, 17). Therefore, deficiency in Mg²⁺ leads to reduced intracellular K⁺. The arrhythmogenic effect of Mg deficiency, as discussed later, may be related to its effect on intracellular K⁺.

Mg has been called nature’s physiologic Ca channel blocker (14). During Mg depletion, intracellular Ca²⁺ rises. This may be the result of both an increase from extracellular Ca²⁺ and release from intracellular Ca²⁺ stores. Mg²⁺ has been demonstrated to decrease the inward Ca²⁺ flux through slow Ca channels (15). In addition, Mg²⁺ decreases the transport of Ca²⁺ out of the sarcoplasmic reticulum into the cell cytosol. Inositol triphosphate (IP₃) has an inverse ability to release Ca²⁺ from intracellular stores in response to changes in Mg²⁺ concentrations, and this also contributes to a rise in intracellular Ca²⁺ during a fall in Mg²⁺ (12).

The distribution of Mg in various body compartments of apparently healthy adult individuals is summarized in Table 9.1. Approximately 60% of Mg is in the skeleton— two thirds is within the hydration shell, and one third is on the crystal surface (18). This may serve as a reservoir for maintaining extracellular and intracellular Mg. Only 1% of Mg is in the extracellular fluid; the rest is intracellular (19).

Mg is compartmentalized within the cell, and most of it is bound to proteins and negatively charged molecules. Significant amounts of Mg are found in the nucleus, mitochondria, the endoplasmic and sarcoplasmic reticulum, and the cytoplasm (5, 6, 20). Total cell Mg concentration has been reported to range between 5 and 20 mM (15). From 90% to 95% of cytosolic Mg is bound to ligands such as ATP, adenosine diphosphate (ADP), citrate, proteins, and nucleic acids. The remainder is free Mg²⁺, constituting 1% to 5% of the total cellular Mg (15, 21).

The concentration of free ionized Mg²⁺ in the cytoplasm of mammalian cells has ranged from 0.5 to 1.0 mM, similar to circulating ionized Mg²⁺ (6, 15). The Mg²⁺ concentration in the cell cytoplasm is maintained relatively constant even when the Mg²⁺ concentration in the extracellular fluid is experimentally varied to either high or low nonphysiologic concentrations (22). The relative constancy of the Mg²⁺ in the intracellular milieu is attributed to the limited permeability of the plasma membrane to Mg and to the operation of specific Mg transport proteins, which regulate the rates at which Mg is taken up or extruded from cells (5, 6, 15). Maintenance of a normal intracellular concentration of Mg²⁺ requires that Mg be actively transported out of the cell (15). Mg transport into or out of cells appears to require the presence of carriermediated transport systems. The efflux of Mg from the cell appears to be coupled to Na transport and requires extrusion of Na by Na⁺/K⁺-ATPase (15). Evidence also indicates a Na-independent efflux of Mg (7, 15). Mg influx appears to be linked to Na transport, but by a different mechanism than efflux (15, 23). At least seven transmembrane Mg²⁺ channels have been cloned (24). These include NIPA2 (25) and MagT1 and TUSC3 (26). Studies of human hereditary diseases (see later) have identified paracellin-1 (claudin 16), claudin 19, and two transient receptor potential channel family members, TRPM6 and TRPM7 (27, 28, 29). TRPM6 is expressed in the kidney, and TRPM7 is constitutively expressed (28). Tissues vary with respect to the rates at which Mg exchange occurs and the percentage of total Mg, which is readily exchangeable (7). The rate of Mg exchange in heart, liver, and kidney exceeds that in skeletal muscle, lymphocytes, red blood cells, brain, and testis.

The processes that maintain or modify the relationships between total and ionized internal and external Mg are incompletely understood. Changes in cytosolic Mg²⁺ regulate some channels (TRPM6 and TRPM7) (24). Mg transport in mammalian cells may be influenced by hormonal and pharmacologic factors (15). Mg²⁺ efflux was stimulated after short-term exposure of isolated perfused rat heart and liver or thymocytes to α and β-agonists and permeant cAMP (30, 31). Activation of protein kinase C by diacylglycerol or by phorbol esters stimulates Mg²⁺ influx and does not alter efflux (32). Epidermal growth factor (EGF) has been shown to increase Mg²⁺ transport into a vascular smooth muscle cell line (33). Insulin and dextrose were found to increase ²⁸Mg uptake by several tissues, including skeletal and cardiac muscle (5, 6). The mechanism of insulin-induced Mg transport is likely the result of an effect on protein kinase C (5, 6). An insulininduced transport of Mg into cells could be one factor responsible for the fall in the serum Mg concentration observed during insulin therapy of diabetic ketoacidosis (34). Investigators have hypothesized that this hormonally regulated Mg uptake system controls intracellular Mg²⁺ concentration in cellular subcytoplasmic compartments. The Mg²⁺ concentration in these compartments would then serve to regulate the activity of Mg-sensitive enzymes. An overall schema of cellular Mg homeostasis is shown in Figure 9.1.

Mineral homeostasis of the individual depends on the amounts ingested, the efficiency of intestinal and renal absorption and excretion, and all other factors affecting them. A schema for human Mg balance is given in Figure 9.2.