Alzheimer's amyloid peptides mediate hypoxic up-regulation of L-type Ca2+ channels.
We examined the effects of chronic hypoxia on recombinant human L-type Ca2+ channel alpha1C subunits stably expressed in HEK 293 cells, using whole-cell patch-clamp recordings. Current density was dramatically increased following 24 h exposure to chronic hypoxia (CH), and membrane channel protein levels were enhanced. CH also increased the levels of Alzheimer's amyloid beta peptides (AbetaPs), determined immunocytochemically. Pharmacological prevention of AbetaP production (via exposure to inhibitors of secretase enzymes that are required to cleave AbetaP from its precursor protein) prevented hypoxic augmentation of currents, as did inhibition of vesicular trafficking with bafilomycin A1. The enhancing effect of AbetaPs or CH were abolished following incubation with the monoclonal 3D6 antibody, raised against the extracellular N' terminus of AbetaP. Immunolocalization and immunoprecipitation studies provided compelling evidence that AbetaPs physically associated with the alpha1C subunit, and this association was promoted by hypoxia. These data suggest an important role for AbetaPs in mediating the increase in Ca2+ channel activity following CH and show that AbetaPs act post-transcriptionally to promote alpha1C subunit insertion into (and/or retention within) the plasma membrane. Such an action will likely contribute to the Ca2+ dyshomeostasis of Alzheimer's disease and may contribute to the mechanisms underlying the known increased incidence of this neurodegenerative disease following hypoxic episodes.
Scragg
Jason L
JL
Institute for Cardiovascular Research, The University of Leeds, Leeds, UK.
Fearon
Ian M
IM
Boyle
John P
JP
Ball
Stephen G
SG
Varadi
Gyula
G
Peers
Chris
C
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D007668:Kidney / Q000737:chemistry / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
D016229:Amyloid beta-Peptides; D020746:Calcium Channels, L-Type; D010455:Peptides