Glucose and endoplasmic reticulum calcium channels regulate HIF-1β via presenilin in pancreatic β-cells
Glucose and endoplasmic reticulum calcium channels regulate HIF-1β via presenilin in pancreatic β-cells
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DOI：
10.1074/jbc.m710601200
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发表时间：
2008-04-11
影响因子：
4.8
通讯作者：
Johnson, James D.
中科院分区：
文献类型：
--
作者：
Dror, Vardit;Kalynyak, Tatyana B.;Johnson, James D.
胰腺 β 细胞死亡是 1 型糖尿病、2 型糖尿病和临床胰岛移植中的关键事件。我们之前已经证明，长期阻断细胞内 Ca2+ 储备的兰尼碱受体 (RyR) 门控释放会激活 β 细胞中钙蛋白酶 10 依赖性细胞凋亡。在本研究中，我们进一步表征了人胰岛和 MIN6 β 细胞系中细胞内 Ca2+ 通道的表达和功能。所有三种 RyR 亚型均在人类胰岛和 MIN6 细胞中得到鉴定，并且在靠近线粒体的位置观察到这些内质网通道。阻断 RyR 通道，但不阻断肌浆/内质网 ATP 酶 (SERCA) 泵，降低 ATP/ADP 比率。阻断Ca2+通过RyR或肌醇三磷酸受体通道的流动，而不是SERCA泵，增加了缺氧诱导因子（HIF-1β）的表达。此外，抑制 RyR 或肌醇三磷酸受体通道（而非 SERCA 泵）会增加早老素-1 的表达。 HIF-1β 和早老素-1 表达也由低葡萄糖诱导。 presenilin-1 的过度表达增加了 HIF-1 beta，表明 HIF 是早老素的下游。我们的结果提供了 β 细胞中早老素-HIF 信号网络的第一个证据。我们证明该途径受 Ca2+ 流经细胞内通道的控制，可能是通过线粒体代谢和 ATP 的变化来控制。这些发现提供了对糖尿病和胰岛移植中细胞内 Ca2+ 稳态和代谢活动受到抑制时激活的信号通路的机制理解。
Pancreatic beta-cell death is a critical event in type 1 diabetes, type 2 diabetes, and clinical islet transplantation. We have previously shown that prolonged block of ryanodine receptor (RyR)-gated release from intracellular Ca2+ stores activates calpain-10-dependent apoptosis in beta-cells. In the present study, we further characterized intracellular Ca2+ channel expression and function in human islets and the MIN6 beta-cell line. All three RyR isoforms were identified in human islets and MIN6 cells, and these endoplasmic reticulum channels were observed in close proximity to mitochondria. Blocking RyR channels, but not sarco/endoplasmic reticulum ATPase (SERCA) pumps, reduced the ATP/ADP ratio. Blocking Ca2+ flux through RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of hypoxia-inducible factor (HIF-1 beta). Moreover, inhibition of RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of presenilin-1. Both HIF-1 beta and presenilin-1 expression were also induced by low glucose. Overexpression of presenilin-1 increased HIF-1 beta, suggesting that HIF is downstream of presenilin. Our results provide the first evidence of a presenilin-HIF signaling network in beta-cells. We demonstrate that this pathway is controlled by Ca2+ flux through intracellular channels, likely via changes in mitochondrial metabolism and ATP. These findings provide a mechanistic understanding of the signaling pathways activated when intracellular Ca2+ homeostasis and metabolic activity are suppressed in diabetes and islet transplantation.