A central role for ROS in the functional remodelling of L-type Ca2+ channels by hypoxia.
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.
Peers
Chris
C
University of Leeds School of Medicine Worsley Building, Leeds LS2 9JT, UK. c.s.peers@leeds.ac.uk
Scragg
Jason L
JL
Boyle
John P
JP
Fearon
Ian M
IM
Taylor
Shafeena C
SC
Green
Kim N
KN
Webster
Nicola J
NJ
Ramsden
Martin
M
Pearson
Hugh A
HA
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*
D000682:Amyloid; D020746:Calcium Channels, L-Type; D017382:Reactive Oxygen Species