Abstract
Although absorption of di‐ and tripeptides into intestinal epithelial cells occurs via the peptide transporter 1 (PEPT1, also called solute carrier family 15 member 1 (SLC15A1)), the detailed regulatory mechanisms are not fully understood. We examined: (a) whether dipeptide absorption in villous enterocytes is associated with a rise in cytosolic Ca2+ ([Ca2+]cyt), (b) whether the calcium sensing receptor (CaSR) is involved in dipeptide‐elicited [Ca2+]cyt signaling, and (c) what potential consequences of [Ca2+]cyt signaling may enhance enterocyte dipeptide absorption. Dipeptide Gly‐Sar and CaSR agonist spermine markedly raised [Ca2+]cyt in villous enterocytes, which was abolished by NPS‐2143, a selective CaSR antagonist and U73122, an phospholipase C (PLC) inhibitor. Apical application of Gly‐Sar induced a jejunal short‐circuit current (Isc), which was reduced by NPS‐2143. CaSR expression was identified in the lamina propria and on the basal enterocyte membrane of mouse jejunal mucosa in both WT and Slc15a1−/− animals, but Gly‐Sar‐induced [Ca2+]cyt signaling was significantly decreased in Slc15a1−/− villi. Clotrimazole and TRM‐34, two selective blockers of the intermediate conductance Ca2+‐activated K+ channel (IKCa), but not iberiotoxin, a selective blocker of the large‐conductance K+ channel (BKCa) and apamin, a selective blocker of the small‐conductance K+ channel (SKCa), significantly inhibited Gly‐Sar‐induced Isc in native tissues. We reveal a novel CaSR‐PLC‐Ca2+‐IKCa pathway in the regulation of small intestinal dipeptide absorption, which may be exploited as a target for future drug development in human nutritional disorders.
Highlights
After dietary proteins are digested to amino acids and di/ tripeptides, they are absorbed into the intestinal epithelial cells (IEC) by a variety of amino acid transporters, and by the proton-coupled di/tripeptide transporter peptide transporter 1 (PEPT1, called solute carrier family 15 member 1 (SLC15A1) (Daniel, 2004; Shen & Matsui, 2018)
We reveal a novel calcium-sensing receptor (CaSR)-phospholipase C (PLC)-Ca2+-intermediate conductance Ca2+-activated K+ channel (IKCa) pathway in the regulation of small intestinal dipeptide absorption, which may be exploited as a target for future drug development in human nutritional disorders
Chen et al previously studied the dependence of murine jejunal dipeptide transport on luminal proton concentration, but they surprisingly found that dipeptides stimulate a similar H+/dipeptide absorption at low and high luminal pH, and that sustained H+/dipeptide absorption rates depend on the maintenance of a negative membrane potential rather than the transmembrane proton gradient
Summary
After dietary proteins are digested to amino acids and di/ tripeptides, they are absorbed into the intestinal epithelial cells (IEC) by a variety of amino acid transporters, and by the proton-coupled di/tripeptide transporter peptide transporter 1 (PEPT1, called solute carrier family 15 member 1 (SLC15A1) (Daniel, 2004; Shen & Matsui, 2018). Deductions from the regulation of other intestinal electrolyte and nutrient absorptive processes suggest that intracellular signaling-dependent events may activate a variety of protein–protein interactions that may enhance the absorptive process, in particular Ca2+-dependent processes such as IP3R-binding protein released with inositol 1,4,5-trisphosphate (IRBIT) translocation (He, Zhang, & Yun, 2008; He et al, 2015) or calcium-sensing receptor (CaSR) activation (Macleod, 2013; Pacheco & Macleod, 2008; Tang et al, 2015b) It is unknown whether intestinal dipeptide absorption results in enterocyte Ca2+ signaling, whether PEPT1-mediated dipeptide transport is involved in dipeptide-elicited Ca2+ signaling and by which mechanisms this may occur, and what the consequences in the regulation of intestinal dipeptide absorption may be. Since [Ca2+]cyt is a critical second cell messenger for the activation of Ca2+sensitive K+ channels, which are one of the key regulators for the maintenance of a negative membrane potential in IEC, we wondered if K+ channels are involved in the luminal absorption of dipeptide; and if so, which type of K+ channels they are
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