eNOS-dependent S-nitrosylation of the NF-κB subunit p65 has neuroprotective effects

Ariel Caviedes, Barbara Maturana, Katherina Corvalán, Alexander Engler, Felipe Gordillo, Manuel Varas-Godoy, Karl Heinz Smalla, Luis Federico Batiz, Carlos Lafourcade, Thilo Kaehne, Úrsula Wyneken

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Cell death by glutamate excitotoxicity, mediated by N-methyl-d-aspartate (NMDA) receptors, negatively impacts brain function, including but not limited to hippocampal neurons. The NF-κB transcription factor (composed mainly of p65/p50 subunits) contributes to neuronal death in excitotoxicity, while its inhibition should improve cell survival. Using the biotin switch method, subcellular fractionation, immunofluorescence, and luciferase reporter assays, we found that NMDA-stimulated NF-κB activity selectively in hippocampal neurons, while endothelial nitric oxide synthase (eNOS), an enzyme expressed in neurons, is involved in the S-nitrosylation of p65 and consequent NF-κB inhibition in cerebrocortical, i.e., resistant neurons. The S-nitro proteomes of cortical and hippocampal neurons revealed that different biological processes are regulated by S-nitrosylation in susceptible and resistant neurons, bringing to light that protein S-nitrosylation is a ubiquitous post-translational modification, able to influence a variety of biological processes including the homeostatic inhibition of the NF-κB transcriptional activity in cortical neurons exposed to NMDA receptor overstimulation.

Original languageEnglish
Article number4
Pages (from-to)4
JournalCell Death and Disease
Volume12
Issue number1
DOIs
StatePublished - 4 Jan 2021

Bibliographical note

Funding Information:
We thank Albert M Galaburda (Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA) for critically reviewing the manuscript. This work was supported by Regular Fondecyt Project 1140108 to U.W. (Conicyt, Chile) and Regular Fondecyt Project 1200693 (ANID, Chile) to U.W. Centrifugation steps were performed thanks to Project Fondequip EQM40131.

Publisher Copyright:
© 2021, The Author(s).

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