Encoding and Transducing the Synaptic or Extrasynaptic Origin of NMDA Receptor Signals to the Nucleus
Encoding and Transducing the Synaptic or Extrasynaptic Origin of NMDA Receptor Signals to the Nucleus
复制标题
将 NMDA 受体信号的突触或突触外起源编码并转导至细胞核
DOI：
10.1016/j.cell.2013.02.002
复制
发表时间：
2013-02-28
期刊：
影响因子：
64.5
通讯作者：
Kreutz, Michael R.
中科院分区：
文献类型：
--
作者：
Karpova, Anna;Mikhaylova, Marina;Kreutz, Michael R.
突触中N-甲基-D-天冬氨酸受体（NMDAR）的激活提供可塑性和细胞存活信号，而驻留在突触外的神经元膜中的NMDAR触发神经变性。目前还不清楚这些相反的信号是如何传递到细胞核并被细胞核识别的。在这项研究中，我们证明，雅各布是一种蛋白质信使，编码突触与突触外NMDAR信号的起源，并将它们传递到细胞核。NMDAR激活仅在突触而非突触外诱导Jacob通过ERK 1/2在丝氨酸-180处磷酸化。长距离运输雅各布从突触，但不是突触外，网站依赖于ERK活性，并与中间丝α-internexin的片段协会阻碍雅各布/ERK复合物在核运输过程中的去磷酸化。在细胞核中，Jacob的磷酸化状态决定了它是否诱导细胞死亡或促进细胞存活并增强突触可塑性。
The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neuro-degeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament alpha-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity.