Zanin Juan P, Montroull Laura E, Volosin Marta, Friedman Wilma J
Department of Biological Sciences, Rutgers University, Newark, NJ, United States.
Front Cell Neurosci. 2019 Oct 29;13:485. doi: 10.3389/fncel.2019.00485. eCollection 2019.
Neurotrophins activate Trk receptor signaling to support neuronal survival and many aspects of neuronal function. Early studies demonstrated that TrkA formed a complex with the p75 neurotrophin receptor (p75 ), which increased the affinity and selectivity of NGF binding, however, whether interaction of p75 with other Trk receptors performs a similar function to enhance ligand binding has not been demonstrated. We investigated the interaction of TrkB with full length p75 in hippocampal neurons in response to BDNF and found that the association of these receptors occurs after ligand binding and requires phosphorylation of TrkB, indicating that formation of this receptor complex was not necessary for ligand binding. Moreover, the interaction of these receptors required internalization and localization to early endosomes. We found that association of TrkB with p75 was necessary for optimal downstream signaling of the PIK-Akt pathway, but not the Erk pathway, in hippocampal neurons. The absence of p75 impaired the ability of BDNF to rescue hippocampal neurons in a trophic deprivation model, suggesting that p75 facilitates the ability of TrkB to activate specific pathways to promote neuronal survival.
神经营养因子激活Trk受体信号传导以支持神经元存活和神经元功能的许多方面。早期研究表明，TrkA与p75神经营养因子受体（p75 ）形成复合物，这增加了NGF结合的亲和力和选择性，然而，p75 与其他Trk受体的相互作用是否执行类似功能以增强配体结合尚未得到证实。我们研究了海马神经元中TrkB与全长p75 对BDNF的反应，发现这些受体的结合发生在配体结合之后，并且需要TrkB的磷酸化，这表明该受体复合物的形成对于配体结合不是必需的。此外，这些受体的相互作用需要内化并定位于早期内体。我们发现，在海马神经元中，TrkB与p75 的结合对于PIK-Akt途径的最佳下游信号传导是必需的，但对于Erk途径则不是。在营养剥夺模型中，p75 的缺失损害了BDNF拯救海马神经元的能力，这表明p75 促进了TrkB激活特定途径以促进神经元存活的能力。
