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ResearchIn-Press PreviewCell biology
Open Access | 10.1172/JCI171249
1Department of Pediatrics, UCSF, San Francisco, United States of America
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1Department of Pediatrics, UCSF, San Francisco, United States of America
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1Department of Pediatrics, UCSF, San Francisco, United States of America
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1Department of Pediatrics, UCSF, San Francisco, United States of America
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1Department of Pediatrics, UCSF, San Francisco, United States of America
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1Department of Pediatrics, UCSF, San Francisco, United States of America
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Cil, O.
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Published November 14, 2023 - More info
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.