title: Chloride channel-targeted therapy for secretory diarrheas.
abstract: Secretory diarrheas caused by bacterial and viral enterotoxins remain a significant cause of morbidity and mortality. Enterocyte Cl(-) channels represent an attractive class of targets for diarrhea therapy, as they are the final, rate-limiting step in enterotoxin-induced fluid secretion in the intestine. Activation of cyclic nucleotide and/or Ca(2+) signaling pathways in secretory diarrheas increases the conductance of Cl(-) channels at the enterocyte luminal membrane, which include the cystic fibrosis transmembrane conductance regulator (CFTR) and Ca(2+)-activated Cl(-) channels (CaCCs). High-throughput screens have yielded several chemical classes of small molecule CFTR and CaCC inhibitors that show efficacy in animal models of diarrheas. Natural-product diarrhea remedies with Cl(-) channel inhibition activity have also been identified, with one product recently receiving FDA approval for HIV-associated diarrhea.
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, CA 94143-0521, USA; Division of Gastroenterology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Thiagarajah
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D003967:Diarrhea / Q000378:metabolism*; D020895:Enterocytes / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism
chemical_list: D018118:Chloride Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator