Small intestinal glucose and sodium absorption through calcium-induced calcium release and store-operated Ca2+ entry mechanisms

Background and Purpose Luminal glucose enhances intestinal Ca2+ absorption through apical Ca(v)1.3 channels necessary for GLUT2-mediated glucose absorption. As these reciprocal mechanisms are not well understood, we investigated 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 using an Ussing chamber, immunocytochemistry and Ca2+ and Na+ imaging in single intestinal epithelial cells. Key Results Glucose induced jejunal I-sc via Na+-glucose cotransporter 1 (SGLT1) operated more efficiently in the presence of extracellular Ca2+. A crosstalk between luminal Ca2+ entry via plasma Ca(v)1.3 channels and the ER Ca2+ release through ryanodine receptor (RYR) activation in small intestinal epithelial cell (IEC) or Ca2+-induced Ca2+ release (CICR) mechanism was involve in Ca2+-mediated jejunal glucose absorption. The ER Ca2+ release through RyR triggered basolateral Ca2+ entry or store-operated Ca2+ entry (SOCE) mechanism and the subsequent Ca2+ entry via Na+/Ca2+ exchanger 1 (NCX1) were found to be critical in Na+-glucose cotransporter-mediated glucose absorption. Blocking RyR, SOCE and NCX1 inhibited glucose induced [Na+](cyt) and [Ca2+](cyt) in single IEC and protein expression and co-localization of STIM1/Orai1, RyR1 and NCX1 were detected in IEC and jejunal mucosa. Conclusion and Implications Luminal Ca2+ influx through Ca(v)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+ signalling. Targeting these mechanisms in IEC may help to modulate blood glucose and sodium in the metabolic disease.

Automated summary

This study found that glucose absorption through Na+-glucose co-transporter 1 in mouse upper jejunal epithelium is more efficient in the presence of extracellular Ca2+. Regulatory mechanisms involving Ca(v)1.3 channels, ER Ca2+ release, SOCE, and NCX1 were critical in modulating intestinal glucose uptake via Ca2+ signaling. Targeting these mechanisms in IEC may help regulate blood glucose and sodium levels in metabolic diseases.