Activation of Trk neurotrophin receptors in the absence of neurotrophins
Activation of Trk neurotrophin receptors in the absence of neurotrophins
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DOI：
10.1073/pnas.061020198
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发表时间：
2001-03-13
影响因子：
11.1
通讯作者：
Chao, MV
中科院分区：
文献类型：
--
作者：
Lee, FS;Chao, MV
神经营养因子通过激活Trk受体酪氨酸激酶调节神经元细胞存活和突触可塑性。神经营养因子与Trk受体的结合导致受体自磷酸化和下游磷酸化级联。在这里，我们描述了一种使用小分子激动剂来反式激活Trk神经营养因子受体的方法，在用腺苷（一种通过G蛋白偶联受体起作用的神经调节剂）处理后观察到PC12细胞中的TrkA受体和海马神经元中的TrkB受体的激活。这些effehs再现使用腺苷激动剂CGS 21680和拮抗剂ZM 241385，表明这种反式激活事件的腺苷涉及腺苷ZA受体; Trk活性的增加可以抑制使用Src家族特异性抑制剂，PP1，或K252a，一种抑制剂的Trk受体。与其他G蛋白偶联受体反式激活事件相反，腺苷使用具有较长时程的Trk受体信号传导。此外，腺苷通过Trk依赖性机制激活磷脂酰肌醇3-激酶/Akt，导致神经生长因子或脑源性神经营养因子撤除后细胞存活增加。因此，通过AZA受体作用的腺苷通过Trk受体的参与发挥营养作用。这些结果通过独特的信号传导机制为腺苷的神经保护作用提供了解释，并提高了小分子可用于引发神经营养作用以治疗神经退行性疾病的可能性。
Neurotrophins regulate neuronal cell survival and synaptic plasticity through activation of Trk receptor tyrosine kinases. Binding of neurotrophins to Trk receptors results in receptor autophosphorylation and downstream phosphorylation cascades. Here, we describe an approach to use small molecule agonists to transactivate Trk neurotrophin receptors, Activation of TrkA receptors in PC12 cells and TrkB in hippocampal neurons was observed after treatment with adenosine, a neuromodulator that acts through G protein-coupled receptors. These effehs were reproduced by using the adenosine agonist CGS 21680 and were counteracted with the antagonist ZM 241385, indicating that this transactivation event by adenosine involves adenosine ZA receptors; The increase in Trk activity could be inhibited by the use of the Src family-specific inhibitor, PP1, or K252a, an inhibitor of Trk receptors. In contrast to other G protein-coupled receptor transactivation events, adenosine used Trk receptor signaling with a longer time course. Moreover, adenosine activated phosphatidylinositol 3-kinase/Akt through a Trk-dependent mechanism that resulted in increased cell survival after nerve growth factor or brain-derived neurotrophic factor withdrawal. Therefore, adenosine acting through the AZA receptors exerts a trophic effect through the engagement of Trk receptors, These results provide an explanation for neuroprotective actions of adenosine through a unique signaling mechanism and raise the possibility that small molecules may be used to elicit neurotrophic effects for the treatment of neurodegenerative diseases.