Detimary P, Gilon P, Henquin J C
Unit of Endocrinology and Metabolism, University of Louvain Faculty of Medicine, UCL 55.30, Avenue Hippocrate 55, B-1200 Brussels, Belgium.
Biochem J. 1998 Jul 15;333 ( Pt 2)(Pt 2):269-74. doi: 10.1042/bj3330269.
In pancreatic beta cells, the increase in the ATP/ADP ratio that follows a stimulation by glucose is thought to play an important role in the Ca2+-dependent increase in insulin secretion. Here we have investigated the possible interactions between Ca2+ and adenine nucleotides in mouse islets. Measurements of both parameters in the same single islet showed that the rise in the ATP/ADP ratio precedes any rise in the cytoplasmic free-Ca2+ concentration ([Ca2+]i) and is already present during the initial transient lowering of [Ca2+]i produced by the sugar. Blockade of Ca2+ influx with nimodipine did not prevent the concentration-dependent increase in the ATP/ADP ratio produced by glucose and even augmented the ratio at all glucose concentrations which normally stimulate Ca2+ influx. In contrast, stimulation of Ca2+ influx by 30 mM K+ or 100 microM tolbutamide lowered the ATP/ADP ratio. This lowering was of rapid onset and reversibility, sustained and prevented by nimodipine or omission of extracellular Ca2+. It was, however, not attenuated after blockade of secretion by activation of alpha2-adrenoceptors. The difference in islet ATP/ADP ratio during blockade and stimulation of Ca2+ influx was similar to that observed between threshold and submaximal glucose concentrations. The results suggest that the following feedback loop could control the oscillations of membrane potential and [Ca2+]i in beta cells. Glucose metabolism increases the ATP/ADP ratio in a Ca2+-independent manner, which leads to closure of ATP-sensitive K+ channels, depolarization and stimulation of Ca2+ influx. The resulting increase in [Ca2+]i causes a larger consumption than production of ATP, which induces reopening of ATP-sensitive K+ channels and arrest of Ca2+ influx. Upon lowering of [Ca2+]i the ATP/ADP ratio increases again and a new cycle may start.
在胰腺β细胞中，葡萄糖刺激后ATP/ADP比值的升高被认为在胰岛素分泌的钙依赖性增加中起重要作用。在此，我们研究了小鼠胰岛中钙与腺嘌呤核苷酸之间可能的相互作用。在同一个单个胰岛中对这两个参数进行测量显示，ATP/ADP比值的升高先于细胞质游离钙浓度（[Ca2+]i）的任何升高，并且在糖引起的[Ca2+]i初始短暂降低期间就已出现。用尼莫地平阻断钙内流并不能阻止葡萄糖引起的ATP/ADP比值的浓度依赖性升高，甚至在所有正常刺激钙内流的葡萄糖浓度下都提高了该比值。相反，30 mM K+或100 μM甲苯磺丁脲刺激钙内流会降低ATP/ADP比值。这种降低起效迅速且可逆，持续存在并被尼莫地平或去除细胞外钙所阻止。然而，通过激活α2肾上腺素能受体阻断分泌后，这种降低并未减弱。阻断和刺激钙内流期间胰岛ATP/ADP比值的差异与在阈值和次最大葡萄糖浓度之间观察到的差异相似。结果表明，以下反馈回路可能控制β细胞中膜电位和[Ca2+]i的振荡。葡萄糖代谢以不依赖钙的方式增加ATP/ADP比值，这导致ATP敏感性钾通道关闭、去极化并刺激钙内流。由此导致的[Ca2+]i升高引起的ATP消耗大于产生，这诱导ATP敏感性钾通道重新开放并阻止钙内流。随着[Ca2+]i降低，ATP/ADP比值再次升高，新的循环可能开始。
