Mg²⁺ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells

Cholera is a global health problem with no targeted therapies. Ca²⁺-sensing receptor (CaSR) is regulator of intestinal ion transport and therapeutic target for diarrhea, and Ca²⁺ is considered its main agonist. We found that increasing extracellular Ca²⁺ had minimal effect on forskolin-induced Cl^- secretion in human intestinal epithelial T84 cells. However, extracellular Mg²⁺, an often-neglected CaSR agonist, suppressed forskolin-induced Cl- secretion in T84 cells by 65% at physiological levels seen in stool (10 mM). Mg²⁺ effect was via CaSR-Gq signaling that leads to cAMP hydrolysis. Mg²⁺ (10 mM) also suppressed Cl^- secretion induced by cholera toxin, heat-stable E. coli enterotoxin and vasoactive intestinal peptide by 50%. In mouse intestinal closed-loops, luminal Mg²⁺ treatment (20 mM) inhibited cholera toxin-induced fluid accumulation by 40%. In mouse intestinal perfusion model of cholera, adding 10 mM Mg²⁺ to the perfusate reversed the net fluid transport from secretion to absorption. These results suggest that Mg²⁺ is the key CaSR activator in mouse and human intestinal epithelia at physiological levels seen in stool. Since stool Mg²⁺ concentrations in cholera patients are essentially zero, oral Mg²⁺ supplementation, alone or in oral rehydration solution (ORS), can be a potential therapy for cholera and other cyclic nucleotide-mediated secretory diarrheas.

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