TrkB Regulates N-Methyl-D-Aspartate Receptor Signaling by Uncoupling and Recruiting the Brain-Specific Guanine Nucleotide Exchange Factor, RasGrf1
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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 (Tyr1472) (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.
KeywordsN-methyl-D-aspartate (NMDA) receptor Ras guanine-nucleotide exchange factor (RasGrf1) Trophomyosin-related kinase B (TrkB) Phosphotyrosine signaling Neurobiology Brain-derived neurotrophic factor (BDNF)
SOM conceived the study. KRB and AT conducted the experiments and all three authors contributed to writing the paper.
This work was supported by a Discovery Grant to Susan O. Meakin from the Natural Sciences and Engineering Research Council of Canada (RGPIN 341947). K. Robinson-Brookes and Asghar Talebian were supported with funds from an Ontario Graduate Scholarship and an Ontario Graduate Scholarship in Science and Technology respectively.
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Conflict of Interest
The authors declare that they have no conflict of interest.
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