TrkB Regulates N-Methyl-D-Aspartate Receptor Signaling by Uncoupling and Recruiting the Brain-Specific Guanine
Asghar Talebian1, Kim Robinson-Brookes2, Susan O Meakin3,4
1Department of Biochemistry, Western University, Medical Sciences Building, Rm 342, 1151 Richmond St. North, London, ON, N6A 5C1, Canada.
Journal of Molecular Neuroscience : MN
|December 15, 2018
Summary
Brain-derived neurotrophic factor (BDNF) receptor TrkB modulates learning and memory by altering NMDA receptor signaling. TrkB uncouples RasGrf1 from NMDA receptors, reducing LTD, and promotes neurite outgrowth for enhanced learning pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Physiology
Background:
- Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are crucial for neuronal function, learning, and memory.
- The precise mechanisms by which TrkB interacts with excitatory ionotropic receptors like the NMDA receptor (NMDAR) remain incompletely understood.
- RasGrf1, a guanine nucleotide exchange factor, is implicated in neurite outgrowth and NMDAR signaling.
Purpose of the Study:
- To elucidate the role of TrkB in modulating NMDAR signaling pathways relevant to learning and memory.
- To investigate the interaction between TrkB, RasGrf1, and NMDAR, specifically the NR2B subunit.
- To determine how TrkB signaling influences processes like long-term depression (LTD) and neurite outgrowth.
Main Methods:
- Investigated the interaction dynamics between RasGrf1, TrkB, and the NR2B subunit of NMDAR.
- Utilized co-stimulation experiments with BDNF and NMDAR agonists.
- Examined the effects of TrkB activation on RasGrf1 and NR2B phosphorylation.
- Assessed changes in NMDA signaling, LTD, and neurite outgrowth.
Main Results:
- NMDAR activation recruits RasGrf1 to the NR2B subunit.
- BDNF co-stimulation with NMDAR activation uncouples RasGrf1 from NR2B and recruits it to TrkB.
- TrkB activation promotes tyrosine phosphorylation of RasGrf1, enhancing neurite outgrowth.
- TrkB activation also leads to tyrosine phosphorylation of NR2B (Tyr1472), facilitating NMDAR cell surface retention.
- These events collectively decrease NMDA signaling associated with LTD and promote signaling pathways linked to learning and memory.
Conclusions:
- TrkB modulates NMDA receptor signaling through a dual mechanism involving RasGrf1.
- TrkB activation uncouples RasGrf1 from NMDAR, thereby reducing LTD.
- Simultaneously, TrkB signaling enhances RasGrf1-mediated neurite outgrowth and signaling pathways crucial for learning and memory.
Keywords:
Brain-derived neurotrophic factor (BDNF)N-methyl-D-aspartate (NMDA) receptorNeurobiologyPhosphotyrosine signalingRas guanine-nucleotide exchange factor (RasGrf1)Trophomyosin-related kinase B (TrkB)More Related Videos
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