Calcium-sensing receptor: A new target for therapy of diarrhea

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.