TGFβ1 downregulates neurite outgrowth, expression of Ca2+ transporters, and mitochondrial dynamics of in vitro cerebellar granule cells
TGFβ1 downregulates neurite outgrowth, expression of Ca2+ transporters, and mitochondrial dynamics of in vitro cerebellar granule cells
复制标题
DOI：
10.1097/wnr.0000000000000106
复制
发表时间：
2014-03-26
期刊：
影响因子：
1.7
通讯作者：
Jurkovicova, Dana
中科院分区：
文献类型：
--
作者：
Jaskova, Katarina;Pavlovicova, Michaela;Jurkovicova, Dana
中枢神经系统（CNS）的急性损伤触发神经退行性过程，可导致严重损伤或功能完全丧失。损伤后，转化生长因子β 1（TGF β 1）的产生增加，并引发纤维化瘢痕的形成，从而阻止受损神经元的正常生长、可塑性和恢复。施用TGF β 1拮抗剂可以预防其病理作用。为了确定增加的TGF β 1释放对CNS神经元中的钙信号传导、神经元可塑性、兴奋性和线粒体动力学的影响，我们将大鼠小脑颗粒神经元的原代培养物直接暴露于TGF β 1。我们集中在细胞内钙转运蛋白，特别是肌醇-1，4，5-三磷酸受体（IP 3R）1型，线粒体动力学和膜兴奋性的表达的变化。TGF β 1显著降低肌醇-1，4，5-三磷酸受体1型的基因和蛋白表达，以及其他细胞内钙转运蛋白如IP（3）R2、兰尼碱受体1型（RyR 1）、RyR 2和SERCA 2的基因表达。改变钙信号抑制轴突生长，并显着减少线粒体的长度和线粒体融合的频率。单个动作电位去极化受到抑制后，小脑颗粒神经元的静息膜电位呈超极化和慢电位。LY 364947，TGF β 1受体I的阻断剂，防止这些作用，和IP 3受体阻断剂2-氨基乙氧基二苯基硼酸酯（2APB）模拟它们。在CNS损伤后，TGF β 1下调细胞内Ca 2+水平并改变损伤神经元内的Ca 2+信号。我们认为，在我们的模型中，TGF β 1可能通过IP 3诱导的Ca 2+信号传导引发神经退行性和神经保护事件。
Acute injury to central nervous system (CNS) triggers neurodegenerative processes that can result in serious damage or complete loss of function. After injury, production of transforming growth factor beta 1 (TGF beta 1) increases and initiates creation of a fibrotic scar that prevents normal growth, plasticity, and recovery of damaged neurons. Administration of TGF beta 1 antagonists can prevent its pathological effects. To define consequences of increased TGF beta 1 release on calcium signaling, neuronal plasticity, excitability, and mitochondrial dynamics in CNS neurons we directly exposed a rat primary culture of cerebellar granule neurons to TGF beta 1. We focused on changes in expression of intracellular calcium transporters, especially inositol-1,4,5-trisphosphate receptor (IP3R) type 1, mitochondrial dynamics, and membrane excitability. TGF beta 1 significantly decreased the gene and protein expression of inositol-1,4,5-trisphosphate receptor type 1 and the gene expression of additional intracellular Ca2+ transporters such as IP(3)R2, ryanodine receptor type 1 (RyR1), RyR2, and SERCA2. Altered calcium signaling suppressed neurite outgrowth and significantly decreased the length of the mitochondria and the frequency of mitochondrial fusion. The resting membrane potential of cerebellar granule neurons was hyperpolarized and slow after depolarization of single action potential was suppressed. LY364947, a blocker of TGF beta 1 receptor I, prevented these effects, and IP3 receptor blocker 2-aminoethoxydiphenyl borate (2APB) mimicked them. After CNS injury TGF beta 1 downregulates intracellular Ca2+ levels and alters Ca2+ signaling within injured neurons. We suggest that in our model TGF beta 1 may trigger both neurodegenerative and neuroprotective events through IP3-induced Ca2+ signaling.