title: Molecular mechanisms of calcium-sensing receptor-mediated calcium signaling in the modulation of epithelial ion transport and bicarbonate secretion.
abstract: Epithelial ion transport is mainly under the control of intracellular cAMP and Ca(2+) signaling. Although the molecular mechanisms of cAMP-induced epithelial ion secretion are well defined, those induced by Ca(2+) signaling remain poorly understood. Because calcium-sensing receptor (CaSR) activation results in an increase in cytosolic Ca(2+) ([Ca(2+)]cyt) but a decrease in cAMP levels, it is a suitable receptor for elucidating the mechanisms of [Ca(2+)]cyt-mediated epithelial ion transport and duodenal bicarbonate secretion (DBS). CaSR proteins have been detected in mouse duodenal mucosae and human intestinal epithelial cells. Spermine and Gd(3+), two CaSR activators, markedly stimulated DBS without altering duodenal short circuit currents in wild-type mice but did not affect DBS and duodenal short circuit currents in cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice. Clotrimazole, a selective blocker of intermediate conductance Ca(2+)-activated K(+) channels but not chromanol 293B, a selective blocker of cAMP-activated K(+) channels (KCNQ1), significantly inhibited CaSR activator-induced DBS, which was similar in wild-type and KCNQ1 knockout mice. HCO3 (-) fluxes across epithelial cells were activated by a CFTR activator, but blocked by a CFTR inhibitor. CaSR activators induced HCO3 (-) fluxes, which were inhibited by a receptor-operated channel (ROC) blocker. Moreover, CaSR activators dose-dependently raised cellular [Ca(2+)]cyt, which was abolished in Ca(2+)-free solutions and inhibited markedly by selective CaSR antagonist calhex 231, and ROC blocker in both animal and human intestinal epithelial cells. Taken together, CaSR activation triggers Ca(2+)-dependent DBS, likely through the ROC, intermediate conductance Ca(2+)-activated K(+) channels, and CFTR channels. This study not only reveals that [Ca(2+)]cyt signaling is critical to modulate DBS but also provides novel insights into the molecular mechanisms of CaSR-mediated Ca(2+)-induced DBS.
authors.affiliation: From the Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China, the Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Zunyi 563003, China, and.
authors.forename: Rui
authors.initials: R
authors.lastname: Xie
authors.affiliation: the Department of Medicine, University of California, San Diego, La Jolla, California 92093.
authors.forename: Xiao
authors.initials: X
authors.lastname: Dong
authors.affiliation: the Department of Medicine, University of California, San Diego, La Jolla, California 92093.
authors.forename: Chase
authors.initials: C
authors.lastname: Wong
authors.affiliation: the Department of Medicine, University of California, San Diego, La Jolla, California 92093, the Veterans Affairs San Diego Healthcare System, La Jolla, California 92161.
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.affiliation: From the Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.affiliation: the Departments of Biochemistry, Internal Medicine (GI), and Microbiology/Immunology, Rush University, Chicago, Illinois 60612.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.affiliation: From the Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China, shimingyang@yahoo.com.
authors.forename: Shiming
authors.initials: S
authors.lastname: Yang
authors.affiliation: From the Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China, the Department of Medicine, University of California, San Diego, La Jolla, California 92093, h2dong@ucsd.ed.
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D004285:Dogs; D004386:Duodenum / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D055724:Electrophysiological Phenomena; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D051379:Mice; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*
chemical_list: D001639:Bicarbonates; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D044169:Receptors, Calcium-Sensing
keywords: Bicarbonate; Calcium; Calcium Channel; Calcium Imaging; Calcium-sensing Receptor; Cytosolic Ca2+ Concentrations; Epithelial Cell; G Protein-Coupled Receptor (GPCR); Receptor-Op; Transepithelial HCO3− secretion