L-histidine sensing by calcium sensing receptor inhibits voltage-dependent calcium channel activity and insulin secretion in β-cells

Life Sci. 2011 Feb 28;88(9-10):440-6. doi: 10.1016/j.lfs.2010.12.022. Epub 2011 Jan 8.


Aims: Our goal was to test the hypothesis that the histidine-induced activation of calcium sensing receptor (CaR) can regulate calcium channel activity of L-type voltage dependent calcium channel (VDCC) due to increased spatial interaction between CaR and VDCC in β-cells and thus modulate glucose-induced insulin secretion.

Main methods: Rat insulinoma (RINr1046-38) insulin-producing β-cells were cultured in RPMI-1640 medium on 25 mm diameter glass coverslips in six-well culture plates in a 5% CO(2) incubator at 37°C. The intracellular calcium concentration, [Ca(2+)](i), was determined by ratio fluorescence microscopy using Fura-2AM. The spatial interactions between CaR and L-type VDCC in β-cells were measured by immunofluorescence confocal microscopy using a Nikon C1 laser scanning confocal microscope. The insulin release was determined by enzyme-linked immunosorbent assay (ELISA).

Key findings: The addition of increasing concentrations of L-histidine along with 10 mM glucose resulted in 57% decrease in [Ca(2+)](i). The confocal fluorescence imaging data showed 5.59 to 8.62-fold increase in colocalization correlation coefficient between CaR and VDCC in β-cells exposed to L-histidine thereby indicating increased membrane delimited spatial interactions between these two membrane proteins. The insulin ELISA data showed 54% decrease in the 1st phase of glucose-induced insulin secretion in β-cells exposed to increasing concentrations of L-histidine.

Significance: L-histidine-induced increased spatial interaction of CaR with VDCC can inhibit calcium channel activity of VDCC and consequently regulate glucose-induced insulin secretion by β-cells. The L-type VDCC could therefore be a potential therapeutic target in diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, L-Type / metabolism*
  • Glucose / pharmacology
  • Histidine / pharmacology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulinoma / pathology
  • Microscopy, Confocal
  • Rats
  • Receptors, Calcium-Sensing / metabolism*
  • Tumor Cells, Cultured


  • Calcium Channels, L-Type
  • Insulin
  • Receptors, Calcium-Sensing
  • Histidine
  • Glucose