title: Neuroprotective effects of reactive oxygen species mediated by BDNF-independent activation of TrkB.
abstract: Reactive oxygen species (ROS) have diverse biological consequences in the mammalian CNS, but the molecular targets mediating these pleiotropic effects are incompletely understood. Like ROS, the neurotrophin receptor, TrkB receptor tyrosine kinase, has diverse effects in the developing and mature mammalian brain. Our discovery that zinc can transactivate TrkB, together with the finding that ROS can trigger zinc release from cytosolic zinc binding proteins, led us to hypothesize that ROS can transactivate TrkB in CNS neurons by a zinc-dependent mechanism. We found that both exogenous H(2)O(2) and endogenous ROS activate TrkB signaling by a Src family kinase-dependent but brain-derived neurotrophic factor-independent mechanism in cultured rat cortical neurons. Exogenous H(2)O(2) enhances cytosolic zinc content in a metallothionein-3 (MT-3)-requiring manner. Both exogenous H(2)O(2) and endogenous ROS mediated transactivation of TrkB requires intracellular zinc and MT-3. The ROS-triggered transactivation of TrkB exerts neuroprotective effects, because inhibition of TrkB kinase activity or uncoupling Shc signaling from TrkB exacerbates neuronal cell death induced by H(2)O(2). Thus, we propose a molecular signaling event whereby ROS induce release of zinc from cytosolic MT-3, the increased cytosolic zinc transactivates TrkB, and the enhanced Shc signaling downstream from TrkB promotes prosurvival effects. We suggest that such neuroprotective effects mediated by ROS are operative in diverse acute and chronic neurological disorders.
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Yang Zhong
authors.initials: YZ
authors.lastname: Huang
authors.forename: James O
authors.initials: JO
authors.lastname: McNamara
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D007202:Indicators and Reagents; D000090023:Metallothionein 3; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000502:physiology; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D020813:Receptor, trkB / Q000819:agonists / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D015032:Zinc / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007202:Indicators and Reagents; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D020813:Receptor, trkB; D019061:src-Family Kinases; D015032:Zinc