Alterations in calcium channel currents underlie defective insulin secretion in a transgenic mouse.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Jan, CR; Ribar, TJ; Means, AR; Augustine, GJ

Published Date

  • June 28, 1996

Published In

Volume / Issue

  • 271 / 26

Start / End Page

  • 15478 - 15485

PubMed ID

  • 8663103

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.271.26.15478


  • eng

Conference Location

  • United States