Review
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 7, 2016; 22(9): 2711-2724
Published online Mar 7, 2016. doi: 10.3748/wjg.v22.i9.2711
Calcium-sensing receptor: A new target for therapy of diarrhea
Sam Xianjun Cheng
Sam Xianjun Cheng, Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL 32610, United States
Author contributions: Cheng SX contributes all to this work.
Supported by The National Institute of Health NICHD, award No. K08HD079674; the CDNHF/NASPGHAN foundation, award No. 00102979, and the Children’s Miracle Network.
Conflict-of-interest statement: The author declares no conflicts of interest for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sam Xianjun Cheng, MD, PhD, Department of Pediatrics, Gastroenterology, Hepatology, and Nutrition, University of Florida, 1600 SW Archer Road, RG 120, PO Box 100296, Gainesville, FL 32610, United States. sam.cheng@ufl.edu
Telephone: +1-352-2739358 Fax: +1-352-2948062
Received: October 13, 2015
Peer-review started: October 14, 2015
First decision: November 13, 2015
Revised: November 18, 2015
Accepted: December 8, 2015
Article in press: December 8, 2015
Published online: March 7, 2016
Processing time: 141 Days and 4.2 Hours
Abstract

Management of acute diarrhea remains a global challenge, particularly in resource-limiting countries. Oral rehydration solution (ORS), a passive rehydrating therapy developed approximately 40 years ago, remains the mainstay treatment. Although ORS is effective for hydration, since it does not inhibit enterotoxin-mediated excessive secretion, reduced absorption and compromised barrier function - the primary mechanisms of diarrhea, ORS does not offer a rapid relief of diarrhea symptom. There are a few alternative therapies available, yet the use of these drugs is limited by their expense, lack of availability and/or safety concerns. Novel anti-diarrheal therapeutic approaches, particularly those simple affordable therapies, are needed. This article explores intestinal calcium-sensing receptor (CaSR), a newly uncovered target for therapy of diarrhea. Unlike others, targeting this host antidiarrheal receptor system appears “all-inclusive”: it is anti-secretory, pro-absorptive, anti-motility, and anti-inflammatory. Thus, activating CaSR reverses changes of both secretory and inflammatory diarrheas. Considering its unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators, it is possible that through targeting of CaSR with a combination of specific nutrients, novel oral rehydrating solutions that are inexpensive and practical to use in all countries may be developed.

Keywords: Secretory diarrhea; Inflammatory diarrhea; Oral rehydration solution; Anti-secretory; Pro-absorptive; Intestinal permeability; Intestinal barrier function; Enteric nervous system; Cholera toxin; Escherichia coli heat stable toxin

Core tip: Diarrheal disease remains a leading cause of death in children and the elderly throughout the world. The cause of death is dehydration secondary to severe diarrhea. Intestinal calcium-sensing receptor (CaSR) is a newly uncovered ancient antidiarrheal receptor system that appears to exert profound effects not only on intestinal secretion, absorption and motility but also on gut permeability and inflammatory responses. Activating this unusual machinery reverses pathophysiological changes of both secretory and inflammatory diarrheas. Considering its unique property of using simple nutrients as activators, it is now possible that through targeting of CaSR and developing novel oral rehydrating solutions that are inexpensive and practical to use in all countries, these diarrhea-associated deaths are reduced or eliminated.