Ca2+ controls slow NAD(P)H oscillations in glucose-stimulated mouse pancreatic islets
Ca2+ controls slow NAD(P)H oscillations in glucose-stimulated mouse pancreatic islets
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DOI：
10.1113/jphysiol.2005.101766
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发表时间：
2006-04-15
影响因子：
5.5
通讯作者：
Polonsky, KS
中科院分区：
文献类型：
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作者：
Luciani, DS;Misler, S;Polonsky, KS
胰岛暴露于生理浓度的葡萄糖导致胰岛素以振荡模式分泌。胰岛素分泌的振荡与胞质Ca 2+浓度的振荡（[Ca 2 +]（c））相关。有证据表明，[Ca 2 +]（c）和分泌的振荡是由代谢的振荡驱动的，但尚不清楚代谢振荡是代谢固有的还是需要Ca 2+反馈。为了解决这个问题，我们使用NAD（P）H自发荧光和[Ca 2 +]（c）的同时记录以及线粒体膜电位（Delta Psi（m））的测量来探索Ca 2+浓度和胰岛代谢的相互作用。所有三个参数均对10 mm葡萄糖产生多相动力学响应，最终以类似于5分钟的周期缓慢振荡。在检查的各种小鼠品系的90%的胰岛中观察到了这一点。NAD（P）H振荡先于[Ca ~（2+）]（c）振荡，但随着[Ca ~（2+）]c的增加，NAD（P）H振荡的上升往往加快，Ca ~（2+）内流是NAD（P）H振荡产生的先决条件。[Ca 2 +]（c）的延长升高在3 mM葡萄糖存在下增强胰岛的NAD（P）H自体荧光，但暴露于10 mM葡萄糖的胰岛的NAD（P）H自体荧光通常降低。[Ca 2 +]（c）去极化Delta Psi（m）的上升相当。[Ca 2 +]（c）升高的NAD（P）H降低效应在线粒体电子传递抑制期间被逆转。这些发现揭示了完整胰岛中NAD（P）H自发荧光的缓慢振荡的存在，并表明它们是由Ca 2+浓度在产生NADH的线粒体酶的激活和Ca 2+诱导的NADH减少之间的动态平衡中形成的。我们建议，后者的一个组成部分反映了线粒体去极化的Ca 2+，减少呼吸控制，从而加速氧化的NADH。
Exposure of pancreatic islets of Langerhans to physiological concentrations of glucose leads to secretion of insulin in an oscillatory pattern. The oscillations in insulin secretion are associated with oscillations in cytosolic Ca2+ concentration ([Ca2+](c)). Evidence suggests that the oscillations in [Ca2+](c) and secretion are driven by oscillations in metabolism, but it is unclear whether metabolic oscillations are intrinsic to metabolism or require Ca2+ feedback. To address this question we explored the interaction of Ca2+ concentration and islet metabolism using simultaneous recordings of NAD(P)H autofluorescence and [Ca2+](c), in parallel with measurements of mitochondrial membrane potential (Delta Psi(m)). All three parameters responded to 10 mm glucose with multiphasic dynamics culminating in slow oscillations with a period of similar to 5 min. This was observed in similar to 90% of islets examined from various mouse strains. NAD(P)H oscillations preceded those of [Ca2+](c), but their upstroke was often accelerated during the increase in [Ca2+]c, and Ca2+ influx was a prerequisite for their generation. Prolonged elevations of [Ca2+](c) augmented NAD(P)H autofluorescence of islets in the presence of 3 mM glucose, but often lowered NAD(P)H autofluorescence of islets exposed to 10 mm glucose. Comparable rises in [Ca2+](c) depolarized Delta Psi(m). The NAD(P)H lowering effect of an elevation of [Ca2+](c) was reversed during inhibition of mitochondrial electron transport. These findings reveal the existence of slow oscillations in NAD(P)H autofluorescence in intact pancreatic islets, and suggest that they are shaped by Ca2+ concentration in a dynamic balance between activation of NADH-generating mitochondrial dehydrogenases and a Ca2+-induced decrease in NADH. We propose that a component of the latter reflects mitochondrial depolarization by Ca2+, which reduces respiratory control and consequently accelerates oxidation of NADH.