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ResearchIn-Press PreviewGastroenterologyTherapeutics Open Access | 10.1172/jci.insight.146823

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

Apurva A. Oak,1 Parth D. Chhetri,1 Amber Rivera,2 Alan S. Verkman,2 and Onur Cil1

1Department of Pediatrics, The University of California San Francisco, San Francisco, United States of America

2Department of Medicine and Physiology, The University of California San Francisco, San Francisco, United States of America

Find articles by Oak, A. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, The University of California San Francisco, San Francisco, United States of America

2Department of Medicine and Physiology, The University of California San Francisco, San Francisco, United States of America

Find articles by Chhetri, P. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, The University of California San Francisco, San Francisco, United States of America

2Department of Medicine and Physiology, The University of California San Francisco, San Francisco, United States of America

Find articles by Rivera, A. in: JCI | PubMed | Google Scholar

1Department of Pediatrics, The University of California San Francisco, San Francisco, United States of America

2Department of Medicine and Physiology, The University of California San Francisco, San Francisco, United States of America

Find articles by Verkman, A. in: JCI | PubMed | Google Scholar |

1Department of Pediatrics, The University of California San Francisco, San Francisco, United States of America

2Department of Medicine and Physiology, The University of California San Francisco, San Francisco, United States of America

Find articles by Cil, O. in: JCI | PubMed | Google Scholar |

Published January 5, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.146823.
Copyright © 2021, Oak et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 5, 2021 - Version history
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Abstract

Diarrhea is a major cause of global mortality, and outbreaks of secretory diarrhea such as cholera remain an important problem in the developing world. Current treatment of secretory diarrhea primarily involves supportive measures such as fluid replacement. The calcium-sensing receptor (CaSR) regulates multiple biological activities in response to changes in extracellular Ca+2. The FDA-approved drug cinacalcet is an allosteric activator of CaSR used for treatment of hyperparathyroidism. Here, we found by short-circuit current measurements in human colonic T84 cells that CaSR activation by cinacalcet reduced forskolin-induced Cl- secretion by greater than 80%. Cinacalcet also reduced Cl- secretion induced by cholera toxin, heat-stable E. coli enterotoxin, and vasoactive intestinal peptide (VIP). The cinacalcet effect primarily involved indirect inhibition of cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl- secretion following activation of CaSR, and downstream phospholipase C and phosphodiesterases. In mice, cinacalcet reduced fluid accumulation by more than 60% in intestinal closed-loop models of cholera and Traveler’s diarrhea. The cinacalcet effect involved both inhibition of CFTR-mediated secretion and stimulation of sodium-hydrogen exchanger 3 (NHE3)-mediated absorption. These findings support the therapeutic utility of the safe and commonly used drug cinacalcet in CFTR-dependent secretory diarrheas including cholera, Traveler’s diarrhea and VIPoma.

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