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. Abbreviations: [Ca 2+ ]cyt, cytosolic Ca 2+ concentration; [Na + ]cyt, cytosolic Na + concentration; 2-APB, 2-aminoethoxydiphenyl borate; CICR, Ca 2+-induced Ca 2+ release; CIRC, calcium-induced calcium release; ER, endoplasmic reticulum; IEC, intestinal epithelial cells; I sc , short-circuit current; NCX1, Na + /Ca 2+ exchanger 1; RyR, ryanodine receptor; SOCE, store-operated Ca 2+ entry; STIM1, stromal interaction molecule 1; TPEN, N,N,N 0 ,N 0-tetrakis(2-pyridylmethyl) ethylenediamine. Fenglian Zhang and Hanxing Wan equally contributed to this work.

Role of Serosal TRPV4-Constituted SOCE Mechanism in Secretagogues-Stimulated Intestinal Epithelial Anion Secretion

“…Our former studies, including T29 (Yang et al, 2018) and SCBN (Zhang et al, 2019;Zhang et al, 2021), confirmed that SOCE/ORAC mechanism is in IECs through SOCE blockers or knockdown cells. IEC-6 cells are usually applied as an IEC model to study intestine epithelial anion secretion (Wenzl et al, 1989), which has also been certificated the participation of SOCE mechanism (Chung et al, 2015).…”

“…We previously demonstrated that carbachol (CCh), a stable chemical analog of neurotransmitter ACh, triggered IP 3 R/ER Ca 2+ release, but caffeine triggered RyR/ER Ca 2+ release, both of which stimulated serosal store-operated Ca 2+ entry (SOCE) mechanism and eventually induced Ca 2+ -dependent duodenal anion secretion (Yang et al, 2018;Zhang et al, 2019;Zhang et al, 2021) However, it is currently unclear: 1) whether [Ca 2+ ] cyt is also a critical cell signaling for other most common and important secretagogues, such as PGE 2 and 5-HT; 2) if serosal SOCE is a universal mechanism for Ca 2+dependent duodenal anion secretion; 3) if so, what molecular components of the SOCE are involved in this process; and 4) if CCh evokes a Ca 2+ -dependent anion secretion when applied from the mucosal side of the duodenum, although it is well known to stimulate it from the serosal side. Therefore, we aimed to investigate these important issues using native duodenal epithelial tissues in mice as a follow-up study.…”

Nuclear Receptor CoRepressors, NCOR1 and SMRT, are required for maintaining systemic metabolic homeostasis

“…As male DKO mice appeared to have a decreased ability to absorb glucose given orally, we next turned to the small intestine for analysis, considering its role in glucose transport and metabolism [ [31] , [32] , [33] ]. Histologic evaluation of the jejunum of the DKO mice that underwent metabolic phenotyping did not reveal any abnormalities ( Figure 6 A), and neither villi length in the jejunum nor total small intestine length was different between control and DKO mice ( Figure 6 B).…”

Ca2+-Permeable Channels/Ca2+ Signaling in the Regulation of Ileal Na+/Gln Co-Transport in Mice

“…As an important second messenger, Ca 2+ is involved in various physiological processes, such as muscle contraction, hormone secretion, and neurotransmitter release. We have previously reported Ca 2+ signaling regulation of ion secretion and absorption through SGLT1 in the intestinal epithelium ( Zhang F. et al, 2019 ; Yinghui et al, 2021 , Zhang et al, 2021 ). We also revealed that Ca 2+ signaling regulates H + /peptide transporter PEPT1 to mediate intestinal Gly-Sar uptake in mice ( Xu et al, 2020 ).…”

“…The Serosal SOCE Mechanism in Ca 2+ -Mediated Gln-I sc Since the store-operated Ca 2+ entry (SOCE) is a well-established mechanism to regulate the Ca 2+ -dependent functions in IEC, including jejunal glucose absorption (Zhang et al, 2021),we examined whether the SOCE mechanism regulates ileal Gln-I sc and started with GdCl 3 , a commonly used SOCE blocker (Zhu et al, 2020). As shown in Figure 6A, serosal addition but not mucosal addition of GdCl 3 (30 µM) inhibited Gln-induced I sc , consistently with the previous finding of the serosal localization of the SOCE (Zhang et al, 2021). Secondly, serosal application of YM-58483 (0.3 µM) and GSK-7975A (100 µM), two selective SOCE blockers with different structures, also reduced Gln-I sc (Figures 6B,C).…”