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...

Full description

Bibliographic Details
Main Authors: Jingyu Xu, Andre Zeug, Brigitte Riederer, Sunil Yeruva, Oliver Griesbeck, Hannelore Daniel, Biguang Tuo, Evgeni Ponimaskin, Hui Dong, Ursula Seidler
Format: Article
Language:English
Published: Wiley 2020-01-01
Series:Physiological Reports
Subjects:
Online Access:https://doi.org/10.14814/phy2.14337
_version_ 1818821212377186304
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.
first_indexed 2024-12-18T23:04:36Z
format Article
id doaj.art-09d1707dcb44404ebd4b97c998297a51
institution Directory Open Access Journal
issn 2051-817X
language English
last_indexed 2024-12-18T23:04:36Z
publishDate 2020-01-01
publisher Wiley
record_format Article
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
work_keys_str_mv AT jingyuxu calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation
AT andrezeug calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation
AT brigitteriederer calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation
AT sunilyeruva calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation
AT olivergriesbeck calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation
AT hanneloredaniel calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation
AT biguangtuo calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation
AT evgeniponimaskin calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation
AT huidong calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation
AT ursulaseidler calciumsensingreceptorregulatesintestinaldipeptideabsorptionviaca2signalingandikcaactivation