A1 Refereed original research article in a scientific journal
The nNOS-p38MAPK Pathway Is Mediated by NOS1AP during Neuronal Death
Authors: Li L, Ginet V, Liu X, Vergun O, Tuittila M, Mathieu M, Bonny C, Puyal J, Truttmann AC, Courtney MJ
Publisher: SOC NEUROSCIENCE
Publication year: 2013
Journal: Journal of Neuroscience
Journal name in source: JOURNAL OF NEUROSCIENCE
Journal acronym: J NEUROSCI
Number in series: 19
Volume: 33
Issue: 19
First page : 8185
Last page: 8201
Number of pages: 17
ISSN: 0270-6474
eISSN: 1529-2401
DOI: https://doi.org/10.1523/JNEUROSCI.4578-12.2013
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/1925852
Neuronal nitric oxide synthase ( nNOS) and p38MAPK are strongly implicated in excitotoxicity, a mechanism common to many neuro-degenerative 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.
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