Alterations in calcium channel currents underlie defective insulin secretion in a transgenic mouse.
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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- Tolbutamide
- Signal Transduction
- Potassium
- Mice, Transgenic
- Mice
- Islets of Langerhans
- Ion Channel Gating
- Insulin Secretion
- Insulin
- Hypoglycemic Agents
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Tolbutamide
- Signal Transduction
- Potassium
- Mice, Transgenic
- Mice
- Islets of Langerhans
- Ion Channel Gating
- Insulin Secretion
- Insulin
- Hypoglycemic Agents