Regulation of hypoxic neuronal death signaling by neuroglobin

Adil A. Khan, Ou Mao Xiao, Surita Banwait, Celine M. DerMardirossian, Gary M. Bokoch, Kunlin Jin, David A. Greenberg

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

The signal transduction pathways involved in neuronal death are not well understood. Neuroglobin (Ngb), a recently discovered vertebrate globin expressed predominantly in the brain, shows increased expression in neurons in response to oxygen deprivation and protects neurons from ischemic and hypoxic death. The mechanism of this neuroprotection is unclear. We examined the surface distribution of raft membrane microdomains in cortical neuron cultures during hypoxia using the raft marker cholera toxin B (CTx-B) subunit. Mechanistically, we demonstrate that hypoxia induces rapid polarization of somal membranes and aggregation of microdomains with the subjacent mitochondrial network. This signaling complex is formed well before neurons commit to die, consistent with an early role in death signal transduction. Neurons from Ngb-overexpressing transgenic (Ngb-Tg) mice do not undergo microdomain polarization or mitochondrial aggregation in response to, and are resistant to death from hypoxia. We link the protective actions of Ngb to inhibition of Pak1 kinase activity and Rac1-GDP-dissociation inhibitor disassociation, and inhibition of actin assembly and death-signaling module polarization.

Original languageEnglish
Pages (from-to)1737-1747
Number of pages11
JournalFASEB Journal
Volume22
Issue number6
DOIs
StatePublished - Jun 2008

Keywords

  • DISC
  • Death-inducing signaling complex
  • Polarity
  • Soma

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