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TrkB Regulates N-Methyl-D-Aspartate Receptor Signaling by Uncoupling and Recruiting the Brain-Specific Guanine Nucleotide Exchange Factor, RasGrf1

  • Asghar Talebian
  • Kim Robinson-Brookes
  • Susan O. Meakin
Article
  • 92 Downloads

Abstract

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.

Keywords

N-methyl-D-aspartate (NMDA) receptor Ras guanine-nucleotide exchange factor (RasGrf1) Trophomyosin-related kinase B (TrkB) Phosphotyrosine signaling Neurobiology Brain-derived neurotrophic factor (BDNF) 

Notes

Author Contribution

SOM conceived the study. KRB and AT conducted the experiments and all three authors contributed to writing the paper.

Funding Information

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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 1.Department of BiochemistryWestern UniversityLondonCanada
  2. 2.Graduate Program in Neuroscience, Western UniversityLondonCanada

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