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- Title
The nNOS-p38MAPK Pathway Is Mediated by NOS1AP during Neuronal Death.
- Authors
Li, Li-Li; Ginet, Vanessa; Xiaonan Liu; Vergun, Olga; Tuittila, Minna; Mathieu, Marc; Bonny, Christophe; Puyal, Julien; Truttmann, Anita C.; Courtney, Michael J.
- 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:NOSl AP interaction and by knockdown with NOSlAP-targeting siRNAs. We designed a cell-permeable peptide that competes for the unique PDZ domain of nNOS that interacts with NOS1 AP. This peptide inhibits NMDA-induced recruitment of NOS1 AP 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:NOSlAP interaction and involvement in excitotoxic signaling may provide future opportunities for generation of neuroprotectants with high specificity.
- Subjects
NITRIC-oxide synthases; CELL death; CELL-mediated cytotoxicity; DIABETES complications; STIMULUS &; response (Biology); CELLULAR signal transduction; MITOGEN-activated protein kinases
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 19, p8185
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.4578-12.2013