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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.