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Volume 271, Number 26, Issue of June 28, 1996 pp. 15478-15485
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Alterations in Calcium Channel Currents Underlie Defective Insulin Secretion in a Transgenic Mouse

(Received for publication, March 4, 1996)

Chung-Ren Jan ^§ , Thomas J. Ribar , Anthony R. Means and George J. Augustine ^§

From the Departments of  Pharmacology and ^§ Neurobiology, Duke University Medical Center, Durham, North Carolina  27710

A transgenic mouse overexpressing a mutant form of calmodulin (CaM-8) that is selectively targeted to pancreatic beta-cells has an impaired ability to secrete insulin in response to elevated blood glucose. Fluorescence measurements of cytosolic Ca²⁺ concentration ([Ca²⁺]_i) showed that intracellular Ca²⁺ rises produced by glucose were smaller than normal in beta-cells of CaM-8 mice. Glucose utilization rates were not different between the CaM-8 and control beta-cells, suggesting that glucose metabolism was unperturbed by CaM-8. Ion channel defects were implicated in the phenotype of CaM-8 beta-cells because treatment of these cells with tolbutamide, a blocker of ATP-sensitive K⁺ channels, produced smaller than normal amounts of insulin secretion and Ca²⁺ rises. Depolarization with elevated extracellular K⁺ also produced smaller Ca²⁺ rises in beta-cells from CaM-8 mice. Whole-cell patch-clamp recordings revealed that Ca²⁺ channel currents of beta-cells from CaM-8 mice were half as large as Ca²⁺ currents in control cells, while the currents carried by delayed rectifier and ATP-sensitive K⁺ channels were similar in magnitude in both cell types. We conclude that expression of the CaM-8 form of calmodulin causes a down-regulation of Ca²⁺ channel currents, which reduces Ca²⁺ entry and accumulation when glucose stimulates closure of the ATP-sensitive K⁺ channels. The reduction in intracellular Ca²⁺ accumulation then prevents an adequate amount of insulin from being secreted from beta-cells of CaM-8 mice.

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