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.