Calcium-sensing receptor regulates intestinal dipeptide absorption via Ca2+ signaling and IKCa activation

Physiol Rep. 2020 Jan;8(1):e14337. doi: 10.14814/phy2.14337.


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.

Keywords: calcium sensing receptor; dipeptide absorption; intestine; intracellular calcium signaling; peptide transporter 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling / genetics
  • Calcium Signaling / physiology*
  • Clotrimazole / pharmacology
  • Dipeptides / metabolism*
  • Dipeptides / pharmacology
  • Enterocytes / drug effects
  • Enterocytes / metabolism*
  • Estrenes / pharmacology
  • Intestinal Absorption / drug effects
  • Intestinal Absorption / physiology*
  • Intestinal Mucosa / metabolism
  • Jejunum / drug effects
  • Jejunum / metabolism*
  • Mice
  • Mice, Knockout
  • Mucous Membrane / metabolism
  • Naphthalenes / pharmacology
  • Peptide Transporter 1 / genetics*
  • Peptide Transporter 1 / metabolism
  • Phosphodiesterase Inhibitors / pharmacology
  • Potassium Channels, Calcium-Activated / antagonists & inhibitors
  • Potassium Channels, Calcium-Activated / metabolism*
  • Pyrrolidinones / pharmacology
  • Receptors, Calcium-Sensing / agonists
  • Receptors, Calcium-Sensing / antagonists & inhibitors
  • Receptors, Calcium-Sensing / metabolism*
  • Spermine / pharmacology
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism


  • Dipeptides
  • Estrenes
  • N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine
  • Naphthalenes
  • Peptide Transporter 1
  • Phosphodiesterase Inhibitors
  • Potassium Channels, Calcium-Activated
  • Pyrrolidinones
  • Receptors, Calcium-Sensing
  • Slc15a1 protein, mouse
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • glycylsarcosine
  • Spermine
  • Type C Phospholipases
  • Clotrimazole