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Originally published In Press as doi:10.1074/jbc.M000090200 on April 5, 2000

J. Biol. Chem., Vol. 275, Issue 25, 18777-18784, June 23, 2000
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The Calcimimetic R-467 Potentiates Insulin Secretion in Pancreatic beta  Cells by Activation of a Nonspecific Cation Channel*

Susanne G. StraubDagger , Bruce KornreichDagger , Robert E. OswaldDagger , Edward F. Nemeth§, and Geoffrey W. G. SharpDagger

From the Dagger  Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14850-6401 and § NPS Pharmaceuticals, Inc., Salt Lake City, Utah 84108

The extracellular, G protein-linked Ca2+-sensing receptor (CaSR), first identified 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 glucose-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 studies with the beta HC9 cell, it was found that the stimulatory effect was due to activation of a nonspecific cation channel, depolarization of the beta -cell, and increased Ca2+ 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 Gi, Go, Gq/11, or Gs. 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.

* This work was supported by National Institutes of Health Grants RO1-DK-42063 and RO1-DK-54243 (to G. W. G. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 607-253-3650; Fax: 607-253-3659; E-mail: gws2@cornell.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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