The calcimimetic R-467 potentiates insulin secretion in pancreatic beta cells by activation of a nonspecific cation channel

The extracellular, G protein-linked Ca2+-sensing receptor (CaSR), first ide ntified in the parathyroid gland, is expressed in several tissues and cells and can be activated by Ca2+ and some other inorganic cations and organic polycations. Calcimimetics such as NPS (R)-N-(3-phenylpropyl)-alpha-methyl- 3-methoxybenzylamine hydrochloride (R-467), a phenylalkylamine, are thought to activate CaSR by allosterically increasing the affinity of the receptor for Ca2+. 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 gluco se-stimulated release. The beta HC9 cell also responded to R-467 and to the enantiomer S-467 with a stimulation of insulin release. In subsequent stud ies with the beta HC9 cell, it was found that the stimulatory effect was du e to activation of a nonspecific cation channel, depolarization of the beta -cell, and increased Ca2+ entry. No other stimulatory mechanism was uncover ed. 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 no t 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 stimulatio n on islets, raises the possibility of a totally new class of drugs that wi ll stimulate insulin secretion during hyperglycemia but which will not caus e hypoglycemia.