NMDA Receptor-Nitric Oxide Transmission Mediates Neuronal Iron Homeostasis via the GTPase Dexras1

Jaime H. Cheah, Sangwon F. Kim, Lynda D. Hester, Kathleen W. Clancy, Stanley E. Patterson, Vassilios Papadopoulos, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

Abstract

Dexras1 is a 30 kDa G protein in the Ras subfamily whose discovery was based on its pronounced inducibility by the glucocorticoid dexamethasone. It binds to neuronal nitric oxide synthase (nNOS) via the adaptor protein CAPON, eliciting S-nitrosylation and activation of Dexras1. We report that Dexras1 binds to the peripheral benzodiazepine receptor-associated protein (PAP7), a protein of unknown function that binds to cyclic AMP-dependent protein kinase and the peripheral benzodiazepine receptor. PAP7 in turn binds to the divalent metal transporter (DMT1), an iron import channel. We have identified a signaling cascade in neurons whereby stimulation of NMDA receptors activates nNOS, leading to S-nitrosylation and activation of Dexras1, which, via PAP7 and DMT1, physiologically induces iron uptake. As selective iron chelation prevents NMDA neurotoxicity in cortical cultures, the NMDA-NO-Dexras1-PAP7-DMT1-iron uptake signaling cascade also appears to mediate NMDA neurotoxicity.

Original languageEnglish (US)
Pages (from-to)431-440
Number of pages10
JournalNeuron
Volume51
Issue number4
DOIs
StatePublished - Aug 17 2006

Keywords

  • MOLNEURO
  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Neuroscience(all)

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