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

Abstract

Background and Purpose Luminal glucose enhances intestinal Ca 2+ 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 [Ca 2+ ] 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 Ca 2+ 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 Ca 2+ . A crosstalk between luminal Ca 2+ entry via plasma Ca v 1.3 channels and the ER Ca 2+ release through ryanodine receptor (RYR) activation in small intestinal epithelial cell (IEC) or Ca 2+ ‐induced Ca 2+ release (CICR) mechanism was involve in Ca 2+ ‐mediated jejunal glucose absorption. The ER Ca 2+ release through RyR triggered basolateral Ca 2+ entry or store‐operated Ca 2+ entry (SOCE) mechanism and the subsequent Ca 2+ entry via Na + /Ca 2+ 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 [Ca 2+ ] 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 Ca 2+ influx through Ca v 1.3 triggers the CICR through RyR1 to deplete the ER Ca 2+ , which induces the basolateral STIM1/Orai1‐mediated SOCE mechanism and the subsequent Ca 2+ entry via NCX1 to regulate intestinal glucose uptake via Ca 2+ signalling. Targeting these mechanisms in IEC may help to modulate blood glucose and sodium in the metabolic disease.

Topics & Concepts