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

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.

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.

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.

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.