Calcium‐sensing receptor regulates intestinal dipeptide absorption via Ca2+ signaling and IKCa activation
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 vi...
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Wiley
2020-01-01
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Online Access: | https://doi.org/10.14814/phy2.14337 |
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author | Jingyu Xu Andre Zeug Brigitte Riederer Sunil Yeruva Oliver Griesbeck Hannelore Daniel Biguang Tuo Evgeni Ponimaskin Hui Dong Ursula Seidler |
author_facet | Jingyu Xu Andre Zeug Brigitte Riederer Sunil Yeruva Oliver Griesbeck Hannelore Daniel Biguang Tuo Evgeni Ponimaskin Hui Dong Ursula Seidler |
author_sort | Jingyu Xu |
collection | DOAJ |
description | 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. |
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issn | 2051-817X |
language | English |
last_indexed | 2024-12-18T23:04:36Z |
publishDate | 2020-01-01 |
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series | Physiological Reports |
spelling | doaj.art-09d1707dcb44404ebd4b97c998297a512022-12-21T20:48:29ZengWileyPhysiological Reports2051-817X2020-01-0181n/an/a10.14814/phy2.14337Calcium‐sensing receptor regulates intestinal dipeptide absorption via Ca2+ signaling and IKCa activationJingyu Xu0Andre Zeug1Brigitte Riederer2Sunil Yeruva3Oliver Griesbeck4Hannelore Daniel5Biguang Tuo6Evgeni Ponimaskin7Hui Dong8Ursula Seidler9Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover GermanyCellular Neurophysiology Hannover Medical School Hannover GermanyDepartment of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover GermanyDepartment of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover GermanyMax‐Planck‐Institut für Neurobiologie Martinsried GermanyNutritional Physiology Technical University of Munich Freising GermanyResearch Gastroenterology Affiliated Hospital of Zunyi Medical University Zunyi ChinaCellular Neurophysiology Hannover Medical School Hannover GermanyDepartment of Medicine University of California, San Diego La Jolla CA USADepartment of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover GermanyAbstract 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.https://doi.org/10.14814/phy2.14337calcium sensing receptordipeptide absorptionintestineintracellular calcium signalingpeptide transporter 1 |
spellingShingle | Jingyu Xu Andre Zeug Brigitte Riederer Sunil Yeruva Oliver Griesbeck Hannelore Daniel Biguang Tuo Evgeni Ponimaskin Hui Dong Ursula Seidler Calcium‐sensing receptor regulates intestinal dipeptide absorption via Ca2+ signaling and IKCa activation Physiological Reports calcium sensing receptor dipeptide absorption intestine intracellular calcium signaling peptide transporter 1 |
title | Calcium‐sensing receptor regulates intestinal dipeptide absorption via Ca2+ signaling and IKCa activation |
title_full | Calcium‐sensing receptor regulates intestinal dipeptide absorption via Ca2+ signaling and IKCa activation |
title_fullStr | Calcium‐sensing receptor regulates intestinal dipeptide absorption via Ca2+ signaling and IKCa activation |
title_full_unstemmed | Calcium‐sensing receptor regulates intestinal dipeptide absorption via Ca2+ signaling and IKCa activation |
title_short | Calcium‐sensing receptor regulates intestinal dipeptide absorption via Ca2+ signaling and IKCa activation |
title_sort | calcium sensing receptor regulates intestinal dipeptide absorption via ca2 signaling and ikca activation |
topic | calcium sensing receptor dipeptide absorption intestine intracellular calcium signaling peptide transporter 1 |
url | https://doi.org/10.14814/phy2.14337 |
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