Current opinion on the regulation of small intestinal magnesium absorption

Figure 1 Magnesium absorption in the small intestine through two absorption pathways. The transcellular transport mechanism involves magnesium (Mg²⁺) influx into enterocytes through the transient receptor potential melastatin 6 homodimer channel (TRPM6), transient receptor potential melastatin 7 homodimer channel (TRPM7), and transient receptor potential melastatin 6/7 heterodimer channel (TRPM6/7). Cystathionine β-synthase domain divalent metal cation transport mediator 4 (CNNM4) mediates basolateral Mg²⁺ extrusion by means of secondary active transport. In the paracellular mechanism, Mg²⁺ moves through tight-associated paracellular pores of Claudin 7 (Cldn 7) and Claudin 12 (Cldn 12).

Figure 2 Fibroblast growth factor-23 and parathyroid hormone regulate magnesium absorption in the small intestine. Fibroblast growth factor-23 (FGF-23) and parathyroid hormone (PTH) act through their corresponding receptors to suppress magnesium absorption in the protein kinase C (PKC)-dependent pathway; they suppressed membrane transient receptor potential melastatin 6 homodimer channel (TRPM6) expression, which leads to the suppression of membrane transient receptor potential melastatin 6/7 (TRPM6/7) expression. FGF-23 and PTH also increase cytosolic cystathionine β-synthase domain divalent metal cation transport mediator 4 (CNNM4) expression. TRPM7: Transient receptor potential melastatin 7 homodimer channel; FGFR: Fibroblast growth factor receptor; PTHR: Parathyroid hormone receptor.

Figure 3 Integrated magnesiotropic action of fibroblast growth factor-23 and parathyroid hormone. Parathyroid hormone (PTH) stimulates the bone resorption process, which increases plasma calcium (Ca²⁺), inorganic phosphate (P_i), and magnesium (Mg²⁺) levels. PTH stimulates the release of 1,25-dihydroxy vitamin D₃ (1,25(OH)₂D₃) to subsequently induce small-intestinal Ca²⁺ absorption. PTH also activates renal tubular Ca²⁺ and Mg²⁺ reabsorption. Plasma Pi and PTH trigger the release of fibroblast growth factor-23 (FGF-23) to abolish 1,25(OH)₂D₃-induced intestinal Ca²⁺ absorption. PTH and FGF-23 synergistically suppress small intestinal absorption of dietary Mg²⁺. PTH and FGF-23 induce urinary P_i excretion.

Figure 4 Ovarian cancer G protein-coupled receptor 1 and acid-sensing ion-channel 1a modulate intestinal magnesium absorption. Activation of ovarian cancer G protein-coupled receptor 1 (OGR1) triggers the phospholipase C (PLC)–protein kinase C (PKC) signaling pathway to activate intestinal magnesium (Mg²⁺) absorption. Activation of acid-sensing ion-channel 1a (ASIC1a) activates intracellular calcium (Ca²⁺) signaling to induce mucosal bicarbonate secretion in a cystic fibrosis transmembrane conductance regulator (CFTR)-dependent mechanism. Secreted bicarbonate (HCO₃⁻) reduces free soluble Mg²⁺ and suppresses intestinal Mg²⁺ absorption. H: Hydrogen.

Figure 5 P2Y₂ purinoceptors modulate intestinal magnesium absorption. Activation of P2Y₂ purinoceptor stimulates luminal cystic fibrosis transmembrane conductance regulator and basolateral Na⁺-HCO₃⁻ cotransporter-1 (NBCe1) activities through a phospholipase C (PLC)-dependent mechanism. Active cystic fibrosis transmembrane conductance regulator (CFTR) and Na⁺-HCO₃⁻ cotransporter-1 induce mucosal bicarbonate (HCO₃⁻) secretion, which reduces luminal free magnesium (Mg²⁺) and suppresses Mg²⁺ absorption. Ca²⁺: Calcium; H: Hydrogen; K: Potassium; Na⁺: Sodium.

Figure 6 Mechanism of proton pump inhibitor-suppressed small intestinal magnesium absorption in proton pump inhibitor-induced hypomagnesemia rats. Proton pump inhibitor (PPI) suppresses membrane transient receptor potential melastatin 7 homodimer channel (TRPM7) and transient receptor potential melastatin 6/7 homodimer channel (TRPM6/7) expression but increases membrane transient receptor potential melastatin 6 homodimer channel (TRPM6) and cystathionine β-synthase domain divalent metal cation transport mediator 4 (CNNM4) expression. PPI induces phosphorylation of the T1851 residue and oxidation of the M1755 residue of the membrane TRPM6 channel, which reduces their channel permeability. These PPI effects reduce transcellular magnesium (Mg²⁺) absorption. Overexpression of claudin 2 (Cldn2), claudin 7 (Cldn7), claudin 12 (Cldn12), and claudin 15 (Cldn15) reduces paracellular permeability, which suppresses paracellular Mg²⁺ absorption. PPI also enhances P2Y₂- and acid-sensing ion-channel 1a (ASIC1a)-suppressed intestinal Mg²⁺ absorption. CFTR: Cystic fibrosis transmembrane conductance regulator; HCO₃⁻: Bicarbonate; NBCe1: Na⁺-HCO₃⁻ cotransporter-1.