Removal of Ca2+ channel β3 Subunit enhances Ca2+ oscillation frequency and insulin exocytosis

被引:94
作者
Berggren, PO [1 ]
Yang, SN
Murakami, M
Efanov, AM
Uhles, S
Köhler, M
Moede, T
Fernström, A
Appelskog, LB
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
Flockerzi, V
机构
[1] Karolinska Univ Hosp SOlna, Karolinska Inst, Dept Mol Med, Rolf Luft Ctr Diabet Res, S-17176 Stockholm, Sweden
[2] Univ Saarland, D-66421 Homburg, Germany
[3] Lilly Res Labs, D-22419 Hamburg, Germany
[4] Moscow MV Lomonosov State Univ, Belozersky Inst Physicochem Biol, Moscow 119899, Russia
[5] Boston Univ, Sch Med, Evans BIomed Res Ctr, Boston, MA 02118 USA
[6] Tech Univ Munich, Inst Pharmakol & Toxikol, D-80802 Munich, Germany
关键词
D O I
10.1016/j.cell.2004.09.033
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 beta(3) subunit in the molecular regulation of these [Ca2+](i) oscillations has now been clarified by using beta(3) subunit-deficient beta cells. beta(3) 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 beta(3) subunit, an effect accounted for by enhanced formation of inositol 1,4,5-trisphosphate (InsP(3)) and increased Ca2+ mobilization from intracellular stores. Hence, the beta(3) subunit negatively modulated InsP(3)-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 beta(3) subunit in the beta cell may constitute the basis for a novel diabetes therapy.
引用
收藏
页码:273 / 284
页数:12
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