title: TrkB interacts with ErbB4 and regulates NRG1-induced NR2B phosphorylation in cortical neurons before synaptogenesis.
abstract: BACKGROUND
  Neuregulin 1 (NRG1) and NMDARs play important roles in various neuronal functions including neural development. NMDARs also promote many cellular events such as proliferation and survival of neuroblasts before synapse formation. Although many recent studies have indicated that NRG1 regulates NMDAR function in cortical neurons, the effect of NRG1 on NMDAR activation before synapse formation is not well studied.
  
  
  RESULTS
  NRG1 induces activation of NMDAR subunit NR2B, and tropomyosin-related kinase receptor B (TrkB), the receptor for BDNF via activation of phospholipase C-gamma (PLC-γ) in immature primary cortical neurons. Our data using TrkB inhibitor (K252a), TrkB siRNA and TrkB-/- neurons demonstrated that TrkB inhibition suppresses NRG1-induced NR2B activation in neurons. We found that NRG1 stimulation leads to GABAA receptor-mediated TrkB activation. Co-immunoprecipitation and proximity ligase assay showed that TrkB interacts with ErbB4 (NRG1 receptor) and the TrkB-ErbB4 interaction was increased following NRG1 treatment. A significant reduction in TrkB-ErbB4 interaction was observed in the prefrontal cortex of schizophrenia subjects. We found significant increase in released BDNF levels following NRG1 treatment, which was inhibited by ErbB4 inhibitor, AG1478. In addition, pretreatment with BDNF neutralizing antibody, but not control IgG abolished NRG1-induced increases in phospho-TrkB and phospho-NR2B levels. Moreover, studies using TrkB mutants showed that intercellular domain of TrkB is necessary for TrkB-ErbB4 interaction and NR2B activation.
  
  
  CONCLUSIONS
  BDNF/TrkB signaling plays an important role in the NRG1-stimulated NR2B regulation. These findings could be of relevance to many neurodevelopmental disorders, as NRG1 and BDNF signaling pathways have been implicated in autism and schizophrenia.
authors: Chirayu D
authors: CD
authors: Pandya
authors: Anilkumar
authors: A
authors: Pillai
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D066247:Receptor, ErbB-4 / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; C121001:NR2B NMDA receptor; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D011799:Quinazolines; D016194:Receptors, N-Methyl-D-Aspartate; D020032:Tyrphostins; C101044:RTKI cpd; C049985:staurosporine aglycone; D066247:Receptor, ErbB-4; D020813:Receptor, trkB; D051966:Phospholipase C gamma