Mitochondrial Ca2+ cycling facilitates activation of the transcription factor NFAT in sensory neurons.
Mitochondrial Ca2+ cycling facilitates activation of the transcription factor NFAT in sensory neurons.
复制标题
DOI：
10.1523/jneurosci.3384-09.2009
复制
发表时间：
2009-09-30
期刊：
影响因子：
--
通讯作者：
Usachev YM
中科院分区：
文献类型：
--
作者：
Kim MS;Usachev YM
Ca 2+依赖的基因调控控制着神经元可塑性的许多方面。在理解电压门控和配体门控Ca 2+通道在触发特异性转录反应中的作用方面已经取得了重大进展。与此相反，在神经元基因调控的功能的重要性，钙缓冲和钙离子转运蛋白是不太清楚，尽管他们的时空控制的钙离子信号的关键贡献。在这里，我们研究了线粒体Ca 2+的摄取和释放的作用，在调节的Ca 2+依赖性转录因子NFAT，已牵连在突触可塑性，轴突生长和神经元的存活。通过动作电位或TRPV 1激动剂强烈刺激感觉神经元诱导NFAT的快速激活和核输入。NFAT的核转位与特征性的长时间[Ca 2 +]i升高（平台期）相关，这是由线粒体的Ca 2+摄取及其随后的释放引起的。使用线粒体Ca 2+指示剂mtPericam进行的测量表明，该过程在整个细胞体中招募线粒体，包括核周区域。[Ca2+]在平台期达到的i水平类似于或高于NFAT激活所需的水平（200-300 nM）。通过阻断线粒体Na+/Ca 2+交换器的Ca 2+释放或通过单向转运体的线粒体Ca 2+摄取来消除[Ca 2 +]i平台，强烈地减少了NFAT的核输入。此外，通过线粒体Na+/Ca 2+交换器阻止Ca 2+动员减少NFAT介导的转录。总的来说，这些数据暗示活动诱导的Ca 2+摄取和线粒体的长期释放作为神经元兴奋-转录偶联的一种新的调节机制。
Ca2+-dependent gene regulation controls many aspects of neuronal plasticity. Significant progress has been made toward understanding the roles of voltage- and ligand-gated Ca2+ channels in triggering specific transcriptional responses. In contrast, the functional importance of Ca2+ buffers and Ca2+ transporters in neuronal gene regulation is less clear despite their critical contribution to the spatio-temporal control of Ca2+ signals. Here we examined the role of mitochondrial Ca2+ uptake and release in regulating the Ca2+-dependent transcription factor NFAT that has been implicated in synaptic plasticity, axonal growth and neuronal survival. Intense stimulation of sensory neurons by action potentials or TRPV1 agonists induced rapid activation and nuclear import of NFAT. Nuclear translocation of NFAT was associated with a characteristic prolonged [Ca2+]i elevation (plateau) that resulted from Ca2+ uptake by, and its subsequent release from mitochondria. Measurements using a mitochondrial Ca2+ indicator, mtPericam, showed that this process recruited mitochondria throughout the cell body, including the perinuclear region. [Ca2+]i levels attained during the plateau phase were similar to or higher than those required for NFAT activation (200–300 nM). The elimination of the [Ca2+]i plateau by blocking either mitochondrial Ca2+ uptake via the uniporter or Ca2+ release via the mitochondrial Na+/Ca2+ exchanger strongly reduced nuclear import of NFAT. Furthermore, preventing Ca2+ mobilization via the mitochondrial Na+/Ca2+ exchanger diminished NFAT-mediated transcription. Collectively, these data implicate activity-induced Ca2+ uptake and prolonged release from mitochondria as a novel regulatory mechanism in neuronal excitation-transcription coupling.