A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä

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




TekijätLi L, Ginet V, Liu X, Vergun O, Tuittila M, Mathieu M, Bonny C, Puyal J, Truttmann AC, Courtney MJ

KustantajaSOC NEUROSCIENCE

Julkaisuvuosi2013

JournalJournal of Neuroscience

Tietokannassa oleva lehden nimiJOURNAL OF NEUROSCIENCE

Lehden akronyymiJ NEUROSCI

Numero sarjassa19

Vuosikerta33

Numero19

Aloitussivu8185

Lopetussivu8201

Sivujen määrä17

ISSN0270-6474

eISSN1529-2401

DOIhttps://doi.org/10.1523/JNEUROSCI.4578-12.2013

Rinnakkaistallenteen osoitehttps://research.utu.fi/converis/portal/detail/Publication/1925852


Tiivistelmä
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.

Ladattava julkaisu

This is an electronic reprint of the original article.
This reprint may differ from the original in pagination and typographic detail. Please cite the original version.





Last updated on 2024-26-11 at 13:59