RGD Reference Report - The nNOS-p38MAPK pathway is mediated by NOS1AP during neuronal death. - Rat Genome Database

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The nNOS-p38MAPK pathway is mediated by NOS1AP during neuronal death.

Authors: Li, LL  Ginet, V  Liu, X  Vergun, O  Tuittila, M  Mathieu, M  Bonny, C  Puyal, J  Truttmann, AC  Courtney, MJ 
Citation: Li LL, etal., J Neurosci. 2013 May 8;33(19):8185-201. doi: 10.1523/JNEUROSCI.4578-12.2013.
RGD ID: 7257606
Pubmed: PMID:23658158   (View Abstract at PubMed)
PMCID: PMC6619617   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.4578-12.2013   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of cellular process  IMP 7257606cortical neuron deathRGD 

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Map2k3  (mitogen activated protein kinase kinase 3)
Nos1ap  (nitric oxide synthase 1 adaptor protein)

Objects referenced in this article
Gene Nos1 nitric oxide synthase 1 Rattus norvegicus

Additional Information