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

Abstract

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 additions 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 1 st 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 potential therapeutic target in diabetes.

Regulator of G Protein Signaling Protein 12 (Rgs12) Controls Mouse Osteoblast Differentiation via Calcium Channel/Oscillation and Gαi-ERK Signaling

“…Yamamura and colleagues reported that Bay K8644 can directly activate CaR, increasing CaR‐mediated cytosolic Ca 2+ concentration. Studies also describe reciprocal relationship between CaR and LTCC due to increased spatial interaction, or change of extracellular calcium . Our results agreed with these finds because Bay K8644 directly increased cytosolic Ca 2+ in Rgs12 f/f OPCs; however, whether CaR involved in cytosolic Ca 2+ restraint after Rgs12 deletion is uncharted in the current study, as well as the deletion effect on LTCC subunits, and more studies are needed.…”

Association Studies of Calcium-Sensing Receptor (CaSR) Polymorphisms with Serum Concentrations of Glucose and Phosphate, and Vascular Calcification in Renal Transplant Recipients

“…Thus, patients who were homozygous for the S986 minor allele had elevations in serum glucose, and this highlights a potential role for the CaSR as a regulator of systemic glucose homeostasis. Indeed, this would be consistent with the reported expression of the CaSR in pancreatic islet beta-cells and that CaSR activation by extracellular calcium or calcimimetic drugs in isolated islets can stimulate beta-cell activity and insulin secretion [ 33 – 35 ]. In addition, the CaSR is expressed and functionally active in adipocytes [ 36 ], and may potentially regulate the peripheral actions of insulin, as highlighted by the finding of an association with the A986S CASR polymorphism and insulin resistance in patients with the polycystic ovarian syndrome [ 37 ].…”

Engendering biased signalling from the calcium‐sensing receptor for the pharmacotherapy of diverse disorders

“…Finally, the CaSR has been detected in pancreatic islet beta‐cells, with evidence suggesting it modulates insulin release (Squires et al ., ; Leech and Habener, ; Gray et al ., ; Parkash and Asotra, ).…”