Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface
Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface
复制标题
DOI：
10.1242/jcs.047712
复制
发表时间：
2009-09
影响因子：
4
通讯作者：
Ling Zhao;Ai-li Sheng;Shu-Hong Huang;Yu-Xia Yin;Bing Chen;Xue-Zhi Li;Yun Zhang;Zhe-yu Chen
中科院分区：
文献类型：
--
作者：
Ling Zhao;Ai-li Sheng;Shu-Hong Huang;Yu-Xia Yin;Bing Chen;Xue-Zhi Li;Yun Zhang;Zhe-yu Chen
酪氨酸激酶受体2型（TrkB受体）的活性依赖性插入质膜可以部分解释脑源性神经营养因子（BDNF）对活性神经元的优先作用;然而，这一过程背后的详细细胞和分子机制仍不清楚。在我们的研究中，我们开发了一种表面TrkB受体的荧光比率测定法，以研究化学长时程增强（cLTP）诱导后TrkB向质膜募集的机制。我们发现，在海马神经元中，cLTP诱导的TrkB表面募集的作用主要发生在具有快速动力学的神经突上（t1/2为2.3分钟），并且依赖于完整的细胞骨架结构。突变研究表明，TrkB的质膜结构域是必要的，并足以使其活性依赖性插入质膜。此外，我们发现，在Ser 478位点的TrkB受体的细胞周期蛋白依赖性激酶5（Cdk 5）的磷酸化是必不可少的cLTP诱导的TrkB插入到神经元表面。最后，cLTP诱导的TrkB表面募集的程度在突触后区域更高，这为突触后对传入BDNF信号的敏感性的快速增强提供了潜在的机制。我们的研究为TrkB受体的神经活性依赖性表面传递提供了新的见解，这将促进我们对TrkB在突触可塑性中的调节作用的理解。
Activity-dependent insertion of tyrosine kinase receptor type 2 (TrkB receptor) into the plasma membrane can explain, in part, the preferential effect of brain-derived neurotrophic factor (BDNF) on active neurons; however, the detailed cellular and molecular mechanisms underlying this process are still unclear. In our study, we developed a fluorescence ratiometric assay for surface TrkB receptors to investigate the mechanisms of recruitment of TrkB to the plasma membrane following chemical long-term potentiation (cLTP) induction. We found that, in hippocampal neurons, the effect of cLTP-induced TrkB surface-recruitment occurred predominantly on neurites with rapid kinetics (t1/2 of ∼2.3 minutes) and was dependent on an intact cytoskeleton structure. Mutagenesis studies revealed that the juxtamembrane domain of TrkB is necessary and sufficient for its activity-dependent insertion into the plasma membrane. Moreover, we found that the phosphorylation of TrkB receptor at the Ser478 site by cyclin-dependent kinase 5 (Cdk5) is essential for cLTP-induced TrkB insertion into the neuronal surface. Finally, the degree of cLTP-induced TrkB surface-recruitment is higher in postsynaptic regions, which provides a potential mechanism for rapid enhancement of postsynaptic sensitivity to incoming BDNF signaling. Our studies provide new insights regarding neuronal activity-dependent surface delivery of TrkB receptor, which will advance our understanding of the modulatory role of TrkB in synaptic plasticity.