TY - JOUR
T1 - Alterations in calcium channel currents underlie defective insulin secretion in a transgenic mouse
AU - Jan, Chung Ren
AU - Ribar, Thomas J.
AU - Means, Anthony R.
AU - Augustine, George J.
PY - 1996
Y1 - 1996
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0029900228&partnerID=8YFLogxK
U2 - 10.1074/jbc.271.26.15478
DO - 10.1074/jbc.271.26.15478
M3 - 文章
C2 - 8663103
AN - SCOPUS:0029900228
SN - 0021-9258
VL - 271
SP - 15478
EP - 15485
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -