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A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
2004 In: Cell Calcium, ISSN 0143-4160, Vol. 35, 357-365 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 35, 357-365 p.
URN: urn:nbn:se:uu:diva-93973OAI: oai:DiVA.org:uu-93973DiVA: diva2:167640
Available from: 2006-02-02 Created: 2006-02-02Bibliographically approved
In thesis
1. Signal Transduction of Glucagon Secretion
Open this publication in new window or tab >>Signal Transduction of Glucagon Secretion
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes mellitus is a bihormonal disorder with hyperglycemia due to deficiency of insulin and hypersecretion of glucagon. To improve diabetes treatment it is important to clarify the signal transduction of glucagon secretion. The cytoplasmic Ca2+ concentration ([Ca2+]i), an important determinant of hormone secretion, and the membrane potential were recorded in individual mouse α-cells. Glucagon and insulin secretion were measured from mouse islets and glucagon secretion from hamster glucagonoma cells. Glucose inhibited glucagon secretion from islets and glucagonoma cells with maximal effect at 7 mM, indicating a direct action on the α-cells. High concentrations of glucose paradoxically stimulated glucagon secretion. Whereas glucose inhibition of glucagon release was associated with lowering of [Ca2+]i, stimulation of secretion at high glucose concentrations was Ca2+-independent. Adrenaline, which is a potent stimulator of glucagon secretion, increased [Ca2+]i by α1- and β-adrenergic mechanisms involving mobilization of intracellular Ca2+ from the endoplasmic reticulum (ER) and influx of the ion across the plasma membrane. Ca2+ mobilization could be attributed to generation of inositol 1,4,5-trisphosphate and cAMP, and influx occurred through voltage-dependent L-type channels activated by a depolarizing store-operated current. Glucose hyperpolarized the α-cells and inhibited adrenaline-induced [Ca2+]i signalling. At 3 mM, glucose had a pronounced stimulatory effect on Ca2+ sequestration in the ER, shutting off store-operated Ca2+ influx. The α-cells express ATP-regulated K+ channels but pharmacological blockade of these channels neither interfered with the hyperpolarizing and [Ca2+]i lowering effects of glucose nor with the inhibition of glucagon secretion. In contrast, activation of the depolarizing store-operated mechanism prevented glucose-induced, hyperpolarization, lowering of [Ca2+]i and inhibition of glucagon secretion. It is proposed that adrenaline stimulation and glucose inhibition of glucagon release involve modulation of a store-operated depolarizing current. The U-shaped dose response relationship for glucose-regulated glucagon secretion may explain the hyperglucagonemia in diabetes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 42 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 103
Cell biology, secretion, glucagon, store-operated channels, calcium, diabetes, Cellbiologi
National Category
Cell Biology
urn:nbn:se:uu:diva-6319 (URN)91-554-6451-3 (ISBN)
Public defence
2006-02-24, Room C2:301, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2006-02-02 Created: 2006-02-02 Last updated: 2011-06-29Bibliographically approved

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