Pancreatic β-cell Na+ channels control global Ca2+ signaling and oxidative metabolism by inducing Na+ and Ca2+ responses that are propagated into mitochondria.
Pancreatic β-cell Na+ channels control global Ca2+ signaling and oxidative metabolism by inducing Na+ and Ca2+ responses that are propagated into mitochondria.
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DOI：
10.1096/fj.13-248161
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Sekler I
中科院分区：
文献类型：
--
作者：
Nita II;Hershfinkel M;Kantor C;Rutter GA;Lewis EC;Sekler I
Na+通道在胰腺β细胞中大量表达，并且易于延长激活。然而，它们在调节细胞Na+通量或线粒体Ca2+瞬变，从而氧化代谢中的作用尚未被探索。在这里，我们结合荧光Na+，Ca2+和ATP成像，电生理分析和通道表达的分子操作来研究Na+通道和线粒体在这些细胞中的通信。我们发现，河豚毒素（TTX）抑制葡萄糖依赖性去极化，阻断胞质Na+和Ca2+的反应和他们的传播到线粒体。TTX敏感的线粒体Ca2+内流在很大程度上被线粒体Ca2+单向转运体MCU表达的敲低所阻断。线粒体Na +/Ca2+交换器（NCLX）的敲低和Na+剂量反应分析表明，NCLX介导线粒体Na+内流，并且被调谐以感测TTX敏感的胞质Na+反应。最后，TTX依赖的线粒体Ca2+升高上调线粒体代谢和增强ATP产生。总之，我们的结果表明，Na+通道启动细胞溶质Na+和Ca2+信号，这些信号通过MCU和NCLX传播到线粒体中，从而形成β细胞中的整体Ca2+瞬变和代谢。
Na+ channels are abundantly expressed in pancreatic β cells and prone to prolonged activation. However, their role in regulating cellular Na+ fluxes or mitochondrial Ca2+ transients, and thereby oxidative metabolism, has not been explored. Here, we combined fluorescent Na+, Ca2+ and ATP imaging, electrophysiological analysis and molecular manipulation of channel expression to study the communication between Na+ channels and mitochondria in these cells. We show that tetrodotoxin (TTX) inhibits glucose-dependent depolarization, blocks cytosolic Na+ and Ca2+ responses and their propagation into mitochondria. TTX-sensitive mitochondrial Ca2+ influx was largely blocked by knockdown of the mitochondrial Ca2+ uniporter, MCU expression. Knockdown of the mitochondrial Na+/Ca2+ exchanger (NCLX), and Na+ dose response analysis, demonstrated that NCLX mediates the mitochondrial Na+ influx and is tuned to sense the TTX-senstive cytosolic Na+ responses. Finally, the TTX-dependent mitochondrial Ca2+ rise upregulated mitochondrial metabolism and enhanced ATP production. Taken together, our results show that Na+ channels initiate cytosolic Na+ and Ca2+ signals that are propagated by MCU and NCLX into mitochondria, thereby shaping both global Ca2+ transients and metabolism in β cells.
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大鼠胰腺B细胞中的Na通道和两种类型的Ca通道用反向溶血斑块测定法鉴定出来。
DOI：
10.1085/jgp.91.5.617
发表时间：
1988-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Hiriart M;Matteson DR
通讯作者：
Matteson DR
DOI：
10.1073/pnas.1210718109
发表时间：
2012-08-07
影响因子：
11.1
作者：
Drago, Ilaria;De Stefani, Diego;Pozzan, Tullio
通讯作者：
Pozzan, Tullio
DOI：
10.1007/978-1-4614-4756-6_33
发表时间：
2013-01-01
期刊：
SODIUM CALCIUM EXCHANGE: A GROWING SPECTRUM OF PATHOPHYSIOLOGICAL IMPLICATIONS
影响因子：
--
作者：
Herchuelz, Andre;Nguidjoe, Evrard;Pachera, Nathalie
通讯作者：
Pachera, Nathalie
内膜的四十千克蛋白是线粒体钙Uniporter。
影响因子：
64.8
作者：
De Stefani, Diego;Raffaello, Anna;Teardo, Enrico;Szabo, Ildiko;Rizzuto, Rosario
通讯作者：
Rizzuto, Rosario
影响因子：
4.8
作者：
Filippin, L;Magalhaes, PJ;Pozzan, T
通讯作者：
Pozzan, T