title: Novel mechanism of increased Ca2+ release following oxidative stress in neuronal cells involves type 2 inositol-1,4,5-trisphosphate receptors.
abstract: Dysregulation of Ca(2+) signaling following oxidative stress is an important pathophysiological mechanism of many chronic neurodegenerative disorders, including Alzheimer's disease, age-related macular degeneration, glaucomatous and diabetic retinopathies. However, the underlying mechanisms of disturbed intracellular Ca(2+) signaling remain largely unknown. We here describe a novel mechanism for increased intracellular Ca(2+) release following oxidative stress in a neuronal cell line. Using an experimental approach that included quantitative polymerase chain reaction, quantitative immunoblotting, microfluorimetry and the optical imaging of intracellular Ca(2+) release, we show that sub-lethal tert-butyl hydroperoxide-mediated oxidative stress result in a selective up-regulation of type-2 inositol-1,4,5,-trisphophate receptors. This oxidative stress mediated change was detected both at the transcriptional and translational level and functionally resulted in increased Ca(2+) release into the nucleoplasm from the membranes of the nuclear envelope at a given receptor-specific stimulus. Our data describe a novel source of Ca(2+) dysregulation induced by oxidative stress with potential relevance for differential subcellular Ca(2+) signaling specifically within the nucleus and the development of novel neuroprotective strategies in neurodegenerative disorders.
authors.affiliation: Department of Ophthalmology and BasicMedical Science, University of Missouri, Kansas City, MO 64108, USA. kajas@umkc.edu
authors.forename: S
authors.initials: S
authors.lastname: Kaja
authors.forename: R S
authors.initials: RS
authors.lastname: Duncan
authors.forename: S
authors.initials: S
authors.lastname: Longoria
authors.forename: J D
authors.initials: JD
authors.lastname: Hilgenberg
authors.forename: A J
authors.initials: AJ
authors.lastname: Payne
authors.forename: N M
authors.initials: NM
authors.lastname: Desai
authors.forename: R A
authors.initials: RA
authors.lastname: Parikh
authors.forename: S L
authors.initials: SL
authors.lastname: Burroughs
authors.forename: E V
authors.initials: EV
authors.lastname: Gregg
authors.forename: D L
authors.initials: DL
authors.lastname: Goad
authors.forename: P
authors.initials: P
authors.lastname: Koulen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D020122:tert-Butylhydroperoxide / Q000633:toxicity
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D020122:tert-Butylhydroperoxide; D002118:Calcium