Guo Wei, Ji Yuanyuan, Wang Shudan, Sun Yun, Lu Bai
Tsinghua-Peking Center for Life Sciences, Beijing, China School of Medicine, Tsinghua University, 1 Qinghuayuan Road, Beijing, 100084, China School of Life Sciences, Tsinghua University, 1 Qinghuayuan Road, Beijing, 100084, China.
GlaxoSmithKline, R&D China, Building 3, 898 Halei Road, Zhangjiang Hi-tech Park, Pudong, Shanghai, 201203, China.
J Cell Sci. 2014 May 15;127(Pt 10):2249-60. doi: 10.1242/jcs.139964. Epub 2014 Mar 14.
Differential kinetics of the same signaling pathway might elicit different cellular outcomes. Here, we show that high-frequency neuronal activity converts BDNF-induced TrkB (also known as NTRK2) signaling from a transient to a sustained mode. A prior depolarization (15 mM KCl, 1 hour) resulted in a long-lasting (>24 hours) activation of the TrkB receptor and its downstream signaling, which otherwise lasts less than an hour. The long-term potentiation (LTP)-inducing theta-burst stimulation but not the long-term depression (LTD)-inducing low-frequency stimulation also induced sustained activation of TrkB. This sustained signaling facilitated dendritic branching and rescued neuronal apoptosis induced by glutamate. The change in TrkB signaling kinetics is mediated by Ca(2+) elevation and CaMKII activation, leading to an increase in TrkB expression on the neuronal surface. Physical exercise also alters the kinetics of TrkB phosphorylation induced by exogenous BDNF. Sustained TrkB signaling might serve as a key mechanism underlying the synergistic effects of neuronal activity and BDNF.
同一信号通路的差异动力学可能引发不同的细胞结果。在此，我们表明高频神经元活动将脑源性神经营养因子（BDNF）诱导的酪氨酸激酶受体B（TrkB，也称为神经营养酪氨酸激酶受体2，NTRK2）信号从瞬时模式转变为持续模式。先前的去极化（15 mM KCl，1小时）导致TrkB受体及其下游信号的长期（>24小时）激活，否则其持续时间不到一小时。诱导长时程增强（LTP）的theta爆发刺激而非诱导长时程抑制（LTD）的低频刺激也诱导了TrkB的持续激活。这种持续信号促进了树突分支，并挽救了由谷氨酸诱导的神经元凋亡。TrkB信号动力学的变化由Ca(2+)升高和CaMKII激活介导，导致神经元表面TrkB表达增加。体育锻炼也会改变外源性BDNF诱导的TrkB磷酸化动力学。持续的TrkB信号可能是神经元活动和BDNF协同作用的关键机制。
