Oscillations of cyclic AMP in hormone-stimulated insulin-secreting β-cells
Oscillations of cyclic AMP in hormone-stimulated insulin-secreting β-cells
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DOI：
10.1038/nature04410
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发表时间：
2006-01-19
期刊：
影响因子：
64.8
通讯作者：
Tengholm, A
中科院分区：
文献类型：
--
作者：
Dyachok, O;Isakov, Y;Tengholm, A
环AMP是一种普遍存在的第二信使，可转导来自多种细胞表面受体的信号以调节多种细胞功能，包括分泌、代谢和基因转录。在胰腺 β 细胞中，cAMP 增强 Ca2+ 依赖性胞吐作用 (1-3)，并介导胰高血糖素和胰高血糖素样肽-1 (GLP-1) 激素释放胰岛素的刺激（参考文献 4-6）。尽管 Ca2+ 信号已被广泛表征并显示涉及对于胰岛素分泌的时间控制很重要的振荡 (4,7,8)，但受体触发的 cAMP 信号的动力学尚不清楚。在这里，我们介绍了一种新的比例倏逝波显微镜方法来测量质膜下的 cAMP 浓度，并表明分泌胰岛素的 β 细胞对胰高血糖素和 GLP-1 做出反应，并伴有明显的 cAMP 振荡。细胞内 Ca2+ 浓度的同时测量表明，这两个信使是相互关联并相互加强的。此外，cAMP 振荡能够诱导快速开关 Ca2+ 反应，但只有 cAMP 浓度持续升高才能诱导 cAMP 依赖性蛋白激酶催化亚基的核转位。我们的结果建立了 cAMP 的新信号传导模式，并表明 cAMP 信号的时间编码可能构成下游细胞靶标差异调节的基础。
Cyclic AMP is a ubiquitous second messenger that transduces signals from a variety of cell surface receptors to regulate diverse cellular functions, including secretion, metabolism and gene transcription. In pancreatic beta-cells, cAMP potentiates Ca2+-dependent exocytosis(1-3) and mediates the stimulation of insulin release exerted by the hormones glucagon and glucagon-like peptide-1 (GLP-1) (refs 4-6). Whereas Ca2+ signals have been extensively characterized and shown to involve oscillations important for the temporal control of insulin secretion(4,7,8), the kinetics of receptor-triggered cAMP signals is unknown. Here we introduce a new ratiometric evanescent-wave-microscopy approach to measure cAMP concentration beneath the plasma membrane, and show that insulin-secreting beta-cells respond to glucagon and GLP-1 with marked cAMP oscillations. Simultaneous measurements of intracellular Ca2+ concentration revealed that the two messengers are interlinked and reinforce each other. Moreover, cAMP oscillations are capable of inducing rapid on-off Ca2+ responses, but only sustained elevation of cAMP concentration induces nuclear translocation of the catalytic subunit of the cAMP-dependent protein kinase. Our results establish a new signalling mode for cAMP and indicate that temporal encoding of cAMP signals might constitute a basis for differential regulation of downstream cellular targets.