LAUSR

BACKGROUND AND PURPOSE It has been observed that luminal glucose enhances intestinal Ca2+ absorption through apical Cav 1.3 channels, which is necessary for GLUT2-mediated glucose absorption. However, the reciprocal regulatory mechanisms of intestinal glucose and Ca2+ absorption are not fully understood. We aimed to study the regulatory mechanisms of intestinal [Ca2+ ]cyt and SGLT1-mediated Na+ -glucose co-transports. EXPERIMENTAL APPROACH Glucose absorption and channel expression were examined in mouse upper jejunal epithelium by Ussing chamber study and immunocytochemistry, respectively. Ca2+ and Na+ imaging was also performed in single intestinal epithelial cells. KEY RESULTS Glucose induced jenunal Isc via Na+ -glucose cotransporter 1 (SGLT1) predominantly, which operated more efficiently in the presence of extracellular Ca2+ . A cross-talk between luminal Ca2+ entry via plasma Cav 1.3 channels and the ER Ca2+ release through ryanodine receptor (RyR) in small intestinal epithelial cell (IEC), or so-called Ca2+ -induced Ca2+ release (CICR) mechanism, was found to involve in Ca2+ -mediated jejunal glucose absorption. Moreover, the ER Ca2+ release through RyR triggered basolateral Ca2+ entry, or so-called store-operated Ca2+ entry (SOCE) mechanism and the subsequent Ca2+ entry via Na+ /Ca2+ exchanger1(NCX1), were found to play critical roles in Na+ -glucose cotransporter-mediated glucose absorption. Indeed, glucose induced [Na+ ]cyt and [Ca2+ ]cyt in single IEC, which was inhibited by selective blockers of RyR, SOCE and NCX1. Finally, the protein expression and co-localization of STIM1/Orai1, RyR1 and NCX1 were detected in IEC and mouse jejunal mucosa. CONCLUSIONS AND IMPLICATIONS Luminal Ca2+ influx through Cav 1.3 triggers the CICR through RyR1 to deplete the ER Ca2+ , which induces the basolateral STIM1/Orai1-mediated SOCE mechanism and the subsequent Ca2+ entry via NCX1 to regulate intestinal glucose uptake via Ca2+ signaling. Targeting the CICR and SOCE mechanisms in IEC may have the potential to modulate both blood glucose and sodium in the metabolic disease.