Department of Biochemistry, Western University, Medical Sciences Building, Rm 342, 1151 Richmond St. North, London, ON, N6A 5C1, Canada.
Graduate Program in Neuroscience, Western University, London, ON, Canada.
J Mol Neurosci. 2019 Jan;67(1):97-110. doi: 10.1007/s12031-018-1214-z. Epub 2018 Dec 13.
Brain-derived neurotrophic factor (BDNF) facilitates multiple aspects of neuronal differentiation and cellular physiology by activating the high-affinity receptor tyrosine kinase, TrkB. While it is known that both BDNF and TrkB modulate cellular processes involved in learning and memory, exactly how TrkB cross-talks and modulates signaling downstream of excitatory ionotropic receptors, such as the NMDA receptor (NMDAR), are not well understood. A model that we have investigated involves the signaling molecule RasGrf1, a guanine nucleotide exchange factor for both Ras and Rac. We previously identified RasGrf1 as a novel Trk binding partner that facilitates neurite outgrowth in response to both nerve growth factor (NGF) (Robinson et al. in J Biol Chem 280:225-235, 2005) and BDNF (Talebian et al. in J Mol Neurosci 49:38-51, 2013); however, RasGrf1 can also bind the NR2B subunit of the NMDAR (Krapivinsky et al. in Neuron 40:775-784, 2003) and stimulate long-term depression (LTD) (Li et al. in J Neurosci 26:1721-1729, 2006). We have addressed a model that TrkB facilitates learning and memory via two processes. First, TrkB uncouples RasGrf1 from NR2B and facilitates a decrease in NMDA signaling associated with LTD (p38-MAPK). Second, the recruitment of RasGrf1 to TrkB enhances neurite outgrowth and pERK activation and signaling associated with learning and memory. We demonstrate that NMDA recruits RasGrf1 to NR2B; however, co-stimulation with BDNF uncouples this association and recruits RasGrf1 to TrkB. In addition, activation of TrkB stimulates the tyrosine phosphorylation of RasGrf1 which increases neurite outgrowth (Talebian et al. in J Mol Neurosci 49:38-51, 2013), and the tyrosine phosphorylation of NR2B (Tyr) (Nakazawa et al. in J Biol Chem 276:693-699, 2001) which facilitates NMDAR cell surface retention (Zhang et al. in J Neurosci 28:415-24, 2008). Collectively, these data demonstrate that TrkB alters NMDA signaling by a dual mechanism that uncouples LTD and, in turn, stimulates neuronal growth and the signaling pathways associated with learning and memory.
脑源性神经营养因子（BDNF）通过激活高亲和力受体酪氨酸激酶 TrkB 促进神经元分化和细胞生理的多个方面。虽然已知 BDNF 和 TrkB 都调节与学习和记忆相关的细胞过程，但 TrkB 如何交叉对话并调节兴奋性离子型受体（如 NMDA 受体（NMDAR））下游的信号转导尚不清楚。我们研究的一个模型涉及信号分子 RasGrf1，它是 Ras 和 Rac 的鸟嘌呤核苷酸交换因子。我们之前发现 RasGrf1 是一种新的 Trk 结合伴侣，可促进神经生长因子（NGF）（Robinson 等人，J Biol Chem 280:225-235, 2005）和 BDNF（Talebian 等人，J Mol Neurosci 49:38-51, 2013）诱导的神经突生长；然而，RasGrf1 也可以与 NMDAR 的 NR2B 亚基结合（Krapivinsky 等人，Neuron 40:775-784, 2003）并刺激长时程抑郁（LTD）（Li 等人，J Neurosci 26:1721-1729, 2006）。我们提出了一个模型，即 TrkB 通过两个过程促进学习和记忆。首先，TrkB 将 RasGrf1 与 NR2B 分离，促进与 LTD（p38-MAPK）相关的 NMDA 信号降低。其次，RasGrf1 被募集到 TrkB 上，增强神经突生长和与学习和记忆相关的 pERK 激活和信号转导。我们证明 NMDA 将 RasGrf1 募集到 NR2B；然而，与 BDNF 的共同刺激会破坏这种关联，并将 RasGrf1 募集到 TrkB。此外，TrkB 的激活刺激 RasGrf1 的酪氨酸磷酸化，从而增加神经突生长（Talebian 等人，J Mol Neurosci 49:38-51, 2013），并促进 NMDA 受体细胞表面保留（Zhang 等人，J Neurosci 28:415-24, 2008）。总之，这些数据表明，TrkB 通过两种机制改变 NMDA 信号转导，即解除 LTD，并反过来刺激神经元生长和与学习和记忆相关的信号通路。
