title: EGFR signaling upregulates surface expression of the GluN2B-containing NMDA receptor and contributes to long-term potentiation in the hippocampus.
abstract: N-methyl-d-aspartate receptors (NMDARs) have been known to be regulated by various receptor tyrosine kinases. Activation of epidermal growth factor receptor (EGFR) specifically increases NMDAR-mediated currents and enhances long-term potentiation (LTP) in the hippocampus. However, the mechanism through which EGFR regulates NMDARs remains to be elucidated. In this study we found that EGFR was highly expressed in the hippocampus and mainly localized in the non-synaptic region including the soma and neurites of cultured hippocampal neurons. EGFR activation led to an increase in ifenprodil-sensitive NMDAR currents. Consistent with this, we also observed that surface expression of GluN2B-containing NMDAR was upregulated. Our biochemical data from hippocampal slices and hippocampal cultured neurons demonstrated that EGF treatment in vitro significantly increased phosphorylation of the GluN2B subunit at Y1472 with a coincidental activation of Src family kinases (SFKs). EGFR blockade with a specific antagonist BIBX-1382 attenuated an increase of GluN2B in the postsynaptic density during high-frequency stimulation (HFS)-induced LTP. Moreover, BIBX blockade significantly impaired HFS-induced LTP. In conclusion, our findings suggest that EGFR signaling upregulates NMDARs through modification of the GluN2B subunit, and is required for HFS-induced LTP in the hippocampus.
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: M
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: X
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: X
authors.initials: X
authors.lastname: Lv
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China. Electronic address: luojianhong@zju.edu.cn.
authors.forename: J
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019061:src-Family Kinases
keywords: EGFR; GluN2B; NMDA receptor; long-term potentiation; phosphorylation; trafficking