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
Language
- eng
Conference Location
- United States