title: Regulation of hypoxic neuronal death signaling by neuroglobin.
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.
authors.affiliation: The Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA. akhan@buckinstitute.org
authors.forename: Adil A
authors.initials: AA
authors.lastname: Khan
authors.forename: Xiao Ou
authors.initials: XO
authors.lastname: Mao
authors.forename: Surita
authors.initials: S
authors.lastname: Banwait
authors.forename: Celine M
authors.initials: CM
authors.lastname: DerMardirossian
authors.forename: Gary M
authors.initials: GM
authors.lastname: Bokoch
authors.forename: Kunlin
authors.initials: K
authors.lastname: Jin
authors.forename: David A
authors.initials: DA
authors.lastname: Greenberg
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors; D000818:Animals; D002540:Cerebral Cortex; D005914:Globins / Q000502:physiology*; D000860:Hypoxia / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000502:physiology*; D000078787:Neuroglobin; D009474:Neurons / Q000473:pathology*; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors
chemical_list: D000199:Actins; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D005914:Globins; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases