The nNOS-p38MAPK Pathway Is Mediated by NOS1AP during Neuronal Death.

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Version: Final published version
Serval ID
serval:BIB_A16767A1B6DF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The nNOS-p38MAPK Pathway Is Mediated by NOS1AP during Neuronal Death.
Journal
Journal of Neuroscience
Author(s)
Li L.L., Ginet V., Liu X., Vergun O., Tuittila M., Mathieu M., Bonny C., Puyal J., Truttmann A.C., Courtney M.J.
ISSN
1529-2401 (Electronic)
ISSN-L
0270-6474
Publication state
Published
Issued date
2013
Volume
33
Number
19
Pages
8185-8201
Language
english
Notes
Publication types: JOURNAL ARTICLE Publication Status: ppublish
Abstract
Neuronal nitric oxide synthase (nNOS) and p38MAPK are strongly implicated in excitotoxicity, a mechanism common to many neurodegenerative conditions, but the intermediary mechanism is unclear. NOS1AP is encoded by a gene recently associated with sudden cardiac death, diabetes-associated complications, and schizophrenia (Arking et al., 2006; Becker et al., 2008; Brzustowicz, 2008; Lehtinen et al., 2008). Here we find it interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulus induces recruitment of NOS1AP to nNOS in rat cortical neuron culture. Excitotoxic activation of p38MAPK and subsequent neuronal death are reduced by competing with the nNOS:NOS1AP interaction and by knockdown with NOS1AP-targeting siRNAs. We designed a cell-permeable peptide that competes for the unique PDZ domain of nNOS that interacts with NOS1AP. This peptide inhibits NMDA-induced recruitment of NOS1AP to nNOS and in vivo in rat, doubles surviving tissue in a severe model of neonatal hypoxia-ischemia, a major cause of neonatal death and pediatric disability. The highly unusual sequence specificity of the nNOS:NOS1AP interaction and involvement in excitotoxic signaling may provide future opportunities for generation of neuroprotectants with high specificity.
Pubmed
Web of science
Open Access
Yes
Create date
20/06/2013 16:49
Last modification date
20/08/2019 15:07
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