title: Adaptor protein APPL1 couples synaptic NMDA receptor with neuronal prosurvival phosphatidylinositol 3-kinase/Akt pathway.
abstract: It is well known that NMDA receptors (NMDARs) can both induce neurotoxicity and promote neuronal survival under different circumstances. Recent studies show that such paradoxical responses are related to the receptor location: the former to the extrasynaptic and the latter to the synaptic. The phosphoinositide 3-kinase (PI3K)/Akt kinase cascade is a key pathway responsible for the synaptic NMDAR-dependent neuroprotection. However, it is still unknown how synaptic NMDARs are coupled with the PI3K/Akt pathway. Here, we explored the role of an adaptor protein-adaptor protein containing pH domain, PTB domain, and leucine zipper motif (APPL1)-in this signal coupling using rat cortical neurons. We found that APPL1 existed in postsynaptic densities and associated with the NMDAR complex through binding to PSD95 at its C-terminal PDZ-binding motif. NMDARs, APPL1, and the PI3K/Akt cascade formed a complex in rat cortical neurons. Synaptic NMDAR activity increased the association of this complex, induced activation of the PI3K/Akt pathway, and consequently protected neurons against starvation-induced apoptosis. Perturbing APPL1 interaction with PSD95 by a peptide comprising the APPL1 C-terminal PDZ-binding motif dissociated the PI3K/Akt pathway from NMDARs. Either the peptide or lentiviral knockdown of APPL1 blocked synaptic NMDAR-dependent recruitment and activation of PI3K/Akt pathway, and consequently blocked synaptic NMDAR-dependent neuroprotection. These results suggest that APPL1 contributes to connecting synaptic NMDARs with the intracellular PI3K/Akt cascade and the downstream prosurvival signaling pathway in rat cortical neurons.
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: Yu-bin
authors.initials: YB
authors.lastname: Wang
authors.forename: Jie-jie
authors.initials: JJ
authors.lastname: Wang
authors.forename: Shao-hua
authors.initials: SH
authors.lastname: Wang
authors.forename: Shuang-Shuang
authors.initials: SS
authors.lastname: Liu
authors.forename: Jing-yuan
authors.initials: JY
authors.lastname: Cao
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Li
authors.forename: Shuang
authors.initials: S
authors.lastname: Qiu
authors.forename: Jian-hong
authors.initials: JH
authors.lastname: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000201:enzymology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C510733:Appl1 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt