1. Removal of Ca2+ channel beta3 subunit enhances Ca2+ oscillation frequency and insulin exocytosis.
- Author
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Berggren PO, Yang SN, Murakami M, Efanov AM, Uhles S, Köhler M, Moede T, Fernström A, Appelskog IB, Aspinwall CA, Zaitsev SV, Larsson O, de Vargas LM, Fecher-Trost C, Weissgerber P, Ludwig A, Leibiger B, Juntti-Berggren L, Barker CJ, Gromada J, Freichel M, Leibiger IB, and Flockerzi V
- Subjects
- Animals, COS Cells, Calcium Channels genetics, Cells, Cultured, Enzyme Inhibitors pharmacology, Glucose metabolism, Homeostasis, Inositol 1,4,5-Trisphosphate metabolism, Inositol 1,4,5-Trisphosphate Receptors, Islets of Langerhans cytology, Islets of Langerhans drug effects, Islets of Langerhans physiology, Mice, Mice, Knockout, Patch-Clamp Techniques, Protein Subunits genetics, Receptors, Cytoplasmic and Nuclear metabolism, Thapsigargin pharmacology, Calcium metabolism, Calcium Channels metabolism, Calcium Signaling physiology, Exocytosis physiology, Insulin metabolism, Protein Subunits metabolism
- Abstract
An oscillatory increase in pancreatic beta cell cytoplasmic free Ca2+ concentration, [Ca2+]i, is a key feature in glucose-induced insulin release. The role of the voltage-gated Ca2+ channel beta3 subunit in the molecular regulation of these [Ca2+]i oscillations has now been clarified by using beta3 subunit-deficient beta cells. beta3 knockout mice showed a more efficient glucose homeostasis compared to wild-type mice due to increased glucose-stimulated insulin secretion. This resulted from an increased glucose-induced [Ca2+]i oscillation frequency in beta cells lacking the beta3 subunit, an effect accounted for by enhanced formation of inositol 1,4,5-trisphosphate (InsP3) and increased Ca2+ mobilization from intracellular stores. Hence, the beta3 subunit negatively modulated InsP3-induced Ca2+ release, which is not paralleled by any effect on the voltage-gated L type Ca2+ channel. Since the increase in insulin release was manifested only at high glucose concentrations, blocking the beta3 subunit in the beta cell may constitute the basis for a novel diabetes therapy.
- Published
- 2004
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