822: Calcium-Sensing Receptor Activator Cinacalcet Reduces Chloride and Fluid Secretion in Mouse and Human Intestinal Organoid Models of Secretory Diarrhea

Chu, Qi Tifany; Yottasan, Pattareeya; Oak, Apurva A.; Chhetri, Parth D.; Lin, Rongheng; Tse, Ming; Donowitz, Mark; Çil, Onur

doi:10.1016/s0016-5085(22)60488-8

Cited by 1 publication

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“…We recently showed that the FDA-approved CaSR activator cinacalcet inhibits CFTR-mediated fluid secretion and promotes NHE3-mediated fluid absorption in human colonic epithelial T84 cells and mouse intestine by promoting cAMP hydrolysis through phosphodiesterases (PDEs). Consistent with this mechanism, cinacalcet was very effective in various mouse models of secretory diarrhea (18,19). Although CaSR activation is a promising treatment strategy for secretory diarrheas, and shortterm cinacalcet use for cholera might provide marked clinical benefits, long-term cinacalcet use for chronic diarrheas can cause systemic side effects due to CaSR activation in other organs.…”

Section: Introductionmentioning

confidence: 82%

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

de Souza Goncalves,

Chu,

Master

et al. 2024

Journal of Clinical Investigation

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Cholera is a global health problem with no targeted therapies. The Ca 2+ -sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for diarrhea, and Ca 2+ is considered its main agonist. We found that increasing extracellular Ca 2+ had a minimal effect on forskolin-induced Cl – secretion in human intestinal epithelial T84 cells. However, extracellular Mg 2+ , an often-neglected CaSR agonist, suppressed forskolin-induced Cl – secretion in T84 cells by 65% at physiological levels seen in stool (10 mM). The effect of Mg 2+ occurred via the CaSR/Gq signaling that led to cAMP hydrolysis. Mg 2+ (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 Mg 2+ treatment (20 mM) inhibited cholera toxin–induced fluid accumulation by 40%. In a mouse intestinal perfusion model of cholera, addition of 10 mM Mg 2+ to the perfusate reversed net fluid transport from secretion to absorption. These results suggest that Mg 2+ is the key CaSR activator in mouse and human intestinal epithelia at physiological levels in stool. Since stool Mg 2+ concentrations in patients with cholera are essentially zero, oral Mg 2+ supplementation, alone or in an oral rehydration solution, could be a potential therapy for cholera and other cyclic nucleotide–mediated secretory diarrheas.

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Section: Introductionmentioning

confidence: 82%