Cholera is a global health problem with no targeted therapies. The Ca²⁺-sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for diarrhea, and Ca²⁺ is considered its main agonist. We found that increasing extracellular Ca²⁺ had a 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). The effect of Mg²⁺ occurred via the CaSR/Gq signaling that led 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 a mouse intestinal perfusion model of cholera, addition of 10 mM Mg²⁺ to the perfusate reversed 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 in stool. Since stool Mg²⁺ concentrations in patients with cholera are essentially zero, oral Mg²⁺ supplementation, alone or in an oral rehydration solution, could be a potential therapy for cholera and other cyclic nucleotide–mediated secretory diarrheas.

中文翻译：

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补充 Mg2+ 通过激活肠上皮细胞中的钙敏感受体治疗小鼠分泌性腹泻

霍乱是一个全球性健康问题，没有针对性的治疗方法。Ca ²⁺感应受体(CaSR) 是肠道离子转运的调节剂和腹泻的治疗靶点，Ca ²⁺被认为是其主要激动剂。我们发现，增加细胞外 Ca ²⁺对毛喉素诱导的人肠上皮 T84 细胞中Cl ^-分泌的影响很小。然而，细胞外 Mg ²⁺是一种经常被忽视的 CaSR 激动剂，在粪便中观察到的生理水平 (10 mM) 中，T84 细胞中毛喉素诱导的 Cl ^-分泌抑制了 65%。^{Mg 2+}的作用通过导致 cAMP 水解的 CaSR/Gq 信号传导发生。Mg ²⁺ (10 mM) 还抑制霍乱毒素、热稳定大肠杆菌诱导的 Cl- 分泌。大肠杆菌肠毒素和血管活性肠肽减少50%。在小鼠肠道闭环中，luminal Mg ²⁺治疗 (20 mM) 可抑制霍乱毒素诱导的液体积聚 40%。在霍乱小鼠肠道灌注模型中，向灌注液中添加 10 mM Mg ^{2+可逆转从分泌到吸收的净液体转运。}这些结果表明，在粪便中的生理水平上，Mg ²⁺是小鼠和人类肠上皮细胞中关键的 CaSR 激活剂。由于霍乱患者粪便 Mg ²⁺浓度基本为零，因此单独或以口服补液溶液形式口服Mg ^{2+补充剂可能是治疗霍乱和其他环核苷酸介导的分泌性腹泻的潜在疗法。}