The Calcimimetic R-467 Potentiates Insulin Secretion in Pancreatic β Cells by Activation of a Nonspecific Cation Channel

The extracellular, G protein-linked Ca 2+ -sensing receptor (CaSR), first identified in the parathyroid gland, is expressed in several tissues and cells and can be activated by Ca 2+ and some other inorganic cations and organic polycations. Calcimimetics such as NPS ( R )- N -(3-phenylpropyl)-α-methyl-3-methoxybenzylamine hydrochloride (R-467), a phenylalkylamine, are thought to activate CaSR by allosterically increasing the affinity of the receptor for Ca 2+ . When tested for its effect on insulin release in C57BL/6 mice, R-467 had no effect under basal conditions but enhanced both phases of glucose-stimulated release. The βHC9 cell also responded to R-467 and to the enantiomer S-467 with a stimulation of insulin release. In subsequent studies with the βHC9 cell, it was found that the stimulatory effect was due to activation of a nonspecific cation channel, depolarization of the β-cell, and increased Ca 2+ entry. No other stimulatory mechanism was uncovered. The depolarization of the cell induced by the calcimimetic could be due to a direct action on the channel or via the CaSR. However, it appeared not to be mediated by G i , G o , G q/11 , or G s . The novel mode of action of the calcimimetic, combined with the glucose-dependence of the stimulation on islets, raises the possibility of a totally new class of drugs that will stimulate insulin secretion during hyperglycemia but which will not cause hypoglycemia.