Removal of Ca2+ channel β3 Subunit enhances Ca2+ oscillation frequency and insulin exocytosis
Removal of Ca2+ channel β3 Subunit enhances Ca2+ oscillation frequency and insulin exocytosis
复制标题
DOI：
10.1016/j.cell.2004.09.033
复制
发表时间：
2004-10-15
期刊：
影响因子：
64.5
通讯作者：
Flockerzi, V
中科院分区：
文献类型：
--
作者：
Berggren, PO;Yang, SN;Flockerzi, V
胰腺β细胞胞浆游离Ca2+浓度的振荡增加，[Ca2+](i)，是葡萄糖诱导的胰岛素释放的关键特征。电压门控Ca2+通道β(3)亚基在这些[Ca2+](i)振荡的分子调节中的作用现在已经通过使用β(3)亚基缺陷β细胞来澄清。由于葡萄糖刺激的胰岛素分泌增加，与野生型小鼠相比，β(3)敲除小鼠表现出更有效的葡萄糖稳态。这是由于缺乏β(3)亚基的β细胞中葡萄糖诱导的[Ca2+](i)振荡频率增加造成的，这种效应是由肌醇1,4,5-三磷酸（InsP(3)）的形成增强和细胞内储存的Ca2+动员增加引起的。因此，β(3)亚基负调节了InsP(3)诱导的Ca2+释放，这与电压门控的L型Ca2+通道的任何影响都不平行。由于胰岛素释放的增加仅在高葡萄糖浓度下表现出来，阻断β细胞中的β(3)亚基可能构成一种新型糖尿病治疗的基础。
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.