Molecular Mechanisms of CaSR-mediated Calcium Signaling in Modulation of Epithelial Ion Transport and Bicarbonate Secretion [Signal Transduction]

October 20th, 2014 by Xie, R., Dong, X., Wong, C., Vallon, V., Tang, B., Sun, J., Yang, S., Dong, H.

Epithelial ion transport is mainly under the control of intracellular cAMP and Ca2+ signaling. While the molecular mechanisms of cAMP-induced epithelial ion secretion are well defined, those induced by Ca2+ signaling remain poorly understood. Since Ca-sensing receptor (CaSR) activation results in an increase in cytosolic Ca2+ ([Ca2+]cyt) but a decrease in cAMP levels, it is a suitable receptor for elucidating the mechanisms of [Ca2+]cyt-mediated epithelial ion transports and duodenal bicarbonate secretion (DBS). CaSR proteins were detected in mouse duodenal mucosae and epithelial cells. Spermine and Gd3+, two CaSR activators, markedly stimulated DBS without altering duodenal Isc in wild type mice, but did not affect DBS and duodenal Isc in cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice. Clotrimazole, a selective blocker of intermediate-conductance Ca2+-activated K+ channels (IKCa), 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 CFTR activator, but blocked by CFTR inhibitor. CaSR activators induced HCO3- fluxes, which were inhibited by receptor-operated channel (ROC) blocker. Moreover, CaSR activators dose-dependently raised cellular [Ca2+]cyt, which was abolished in Ca2+-free solutions and markedly inhibited by selective CaSR antagonist calhex 231, and ROC blocker. Taken together, CaSR activation triggers Ca2+-dependent DBS likely through the ROC, IKCa and CFTR channels. The present study not only reveals that [Ca2+]cyt is a critical signaling to modulate DBS, but also provides novel insights into the molecular mechanisms of CaSR-mediated Ca2+-induced DBS.
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