Regulation of mitochondrial calcium signaling by Pannexin2

泛联蛋白是一种通道蛋白， 与间隙连接蛋白的连接蛋白家族相关。与连接蛋白不同， 不从两个相邻细胞之间的链接，而是直接连接到外部 细胞的环境。然而，我们最近发现， pannexins，Panx2，仅限于细胞内部。最重要的是， 它与细胞的能量来源线粒体密切相关。 线粒体的缺陷与 包括阿尔茨海默氏症和帕金森氏症在内的脑部疾病。由于泛连接蛋白 据报道，通道可渗透钙离子，我们假设 在正常情况下，Panx2通道活性调节线粒体 通过调节线粒体钙水平来产生能量。与此相反的是， 在病理条件下，Panx 2通道活性的失调触发 线粒体钙超载导致细胞死亡。我们打算测试一下 三个相互关联的目标。在目标1中，我们将研究 线粒体能量产生的改变将导致Panx 2的变化。 表达和分布。如果Panx2的增加与 线粒体功能障碍，我们将确定Panx2是否调节线粒体功能障碍。 目标2中能量分子ATP的产生。在确认了关键作用之后 Panx2在线粒体信号传导中的作用，我们将研究Panx2活性是否 影响Aim 3中线粒体钙水平。我们提案的结果 将揭示减少线粒体功能障碍的新策略， 为脑部疾病的可能治疗干预奠定基础。

Pannexins are channel proteins that are related to the connexin family of gap junction proteins. Unlike connexins, pannexins do not from a link between two adjacent cells but connect directly to the external environment of the cells. However, we recently showed that one member of the pannexins, Panx2, is restricted to the interior of the cell. Most importantly, it is closely associated with mitochondria, the energy powerhouse of the cell. Defects in mitochondria are implicated in brain disorders including Alzheimer’s and Parkinson’s disease. Since pannexin channels have been reported to be permeable to calcium ions, we hypothesize that under normal conditions Panx2 channel activity regulate mitochondrial energy production by regulating mitochondrial calcium levels. In contrast, under pathological conditions, dysregulation of Panx2 channel activity triggers mitochondrial calcium overload leading to cell death. We propose to test this hypothesis in three interrelated aims. In Aim 1, we will examine whether alteration of mitochondrial energy production will lead to changes in Panx2 expression and distribution. If an increase in Panx2 is related to mitochondrial dysfunction, we will determine whether Panx2 modulates the production of energy molecule ATP in Aim 2. After confirming the critical role of Panx2 in mitochondrial signaling, we will investigate whether Panx2 activity influences the level mitochondrial calcium in Aim 3. Findings from our proposal will reveal novel strategies to curtail mitochondrial dysfunction and lay the foundation of possible therapeutic interventions in brain diseases.