Hayer Stefanie N, Bading Hilmar
From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
From the Department of Neurobiology, Interdisciplinary Center for Neurosciences, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany
J Biol Chem. 2015 Feb 27;290(9):5523-32. doi: 10.1074/jbc.M113.532010. Epub 2014 Dec 19.
Calcium transients in the cell nucleus evoked by synaptic activity in hippocampal neurons function as a signaling end point in synapse-to-nucleus communication. As an important regulator of neuronal gene expression, nuclear calcium is involved in the conversion of synaptic stimuli into functional and structural changes of neurons. Here we identify two synaptic organizers, Lrrtm1 and Lrrtm2, as targets of nuclear calcium signaling. Expression of both Lrrtm1 and Lrrtm2 increased in a synaptic NMDA receptor- and nuclear calcium-dependent manner in hippocampal neurons within 2-4 h after the induction of action potential bursting. Induction of Lrrtm1 and Lrrtm2 occurred independently of the need for new protein synthesis and required calcium/calmodulin-dependent protein kinases and the nuclear calcium signaling target CREB-binding protein. Analysis of reporter gene constructs revealed a functional cAMP response element in the proximal promoter of Lrrtm2, indicating that at least Lrrtm2 is regulated by the classical nuclear Ca(2+)/calmodulin-dependent protein kinase IV-CREB/CREB-binding protein pathway. These results suggest that one mechanism by which nuclear calcium signaling controls neuronal network function is by regulating the expression of Lrrtm1 and Lrrtm2.
海马神经元突触活动诱发的细胞核钙瞬变，在突触到细胞核的通讯中作为信号传导终点发挥作用。作为神经元基因表达的重要调节因子，细胞核钙参与将突触刺激转化为神经元的功能和结构变化。我们在此确定了两种突触组织者Lrrtm1和Lrrtm2，作为细胞核钙信号传导的靶点。在动作电位爆发诱导后2至4小时内，海马神经元中Lrrtm1和Lrrtm2的表达均以突触NMDA受体和细胞核钙依赖的方式增加。Lrrtm1和Lrrtm2的诱导独立于新蛋白质合成的需求，并且需要钙/钙调蛋白依赖性蛋白激酶以及细胞核钙信号传导靶点CREB结合蛋白。对报告基因构建体的分析揭示了Lrrtm2近端启动子中存在功能性cAMP反应元件，表明至少Lrrtm2受经典的细胞核Ca(2+)/钙调蛋白依赖性蛋白激酶IV-CREB/CREB结合蛋白途径调控。这些结果表明，细胞核钙信号传导控制神经元网络功能的一种机制是通过调节Lrrtm1和Lrrtm2的表达。
