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

Figure 1

Illustrates the four common pathways leading to formation of diarrhea. The four pathways are: A: Impaired absorption (cause of osmotic diarrhea); B: Excessive secretion (leading to secretory diarrhea); C: Breakdown of intestinal barrier and enhanced inflammation (implicated in inflammatory diarrhea); D: Overly active enteric nervous system (presumed cause of neurogenic diarrhea seen in irritable bowel syndrome). Note that while most current antidiarrheal therapeutics (green-colored) target one individual pathway, CaSR activators (red-colored) have the potential of correcting changes in all the four diarrhea-causing pathways. CaCC: Calcium-activated chloride channel; CaSR: Calcium-sensing receptor; CFTR: Cystic fibrosis transmembrane conductance regulator; CTX: Cholera toxin; ORS: Oral rehydration solution; PDE: Phosphodiesterase; PG: Prostaglandin; SCFA: Short-chain fatty acid; STa: Heat stable toxin; VIP: Vasoactive intestinal peptide.