title: A central role for ROS in the functional remodelling of L-type Ca2+ channels by hypoxia.
abstract: Periods of prolonged hypoxia are associated clinically with an increased incidence of dementia, the most common form of which is Alzheimer's disease. Here, we review recent studies aimed at providing a cellular basis for this association. Hypoxia promoted an enhanced secretory response of excitable cells via formation of a novel Ca2+ influx pathway associated with the formation of amyloid peptides of Alzheimer's disease. More strikingly, hypoxia potentiated Ca2+ influx specifically through L-type Ca2+ channels in three distinct cellular systems. This effect was post-transcriptional, and evidence suggests it occurred via increased formation of amyloid peptides which alter Ca2+ channel trafficking via a mechanism involving increased production of reactive oxygen species by mitochondria. This action of hypoxia is likely to contribute to dysregulation of Ca2+ homeostasis, which has been proposed as a mechanism of cell death in Alzheimer's disease. We suggest, therefore, that our data provide a cellular basis to account for the known increased incidence of Alzheimer's disease in patients who have suffered prolonged hypoxic episodes.
authors.affiliation: University of Leeds School of Medicine Worsley Building, Leeds LS2 9JT, UK. c.s.peers@leeds.ac.uk
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
authors.forename: Jason L
authors.initials: JL
authors.lastname: Scragg
authors.forename: John P
authors.initials: JP
authors.lastname: Boyle
authors.forename: Ian M
authors.initials: IM
authors.lastname: Fearon
authors.forename: Shafeena C
authors.initials: SC
authors.lastname: Taylor
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Webster
authors.forename: Martin
authors.initials: M
authors.lastname: Ramsden
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Pearson
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D003704:Dementia / Q000378:metabolism / Q000503:physiopathology*; D005089:Exocytosis / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008928:Mitochondria / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000682:Amyloid; D020746:Calcium Channels, L-Type; D017382:Reactive Oxygen Species