Alzheimer's amyloid peptides mediate hypoxic up-regulation of L-type Ca²⁺ channels

ABSTRACT We examined the effects of chronic hypoxia on recombinant human L‐type Ca2+ channel α1C 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 β peptides (AβPs), determined immunocytochemically. Pharmacological prevention of AβP production (via exposure to inhibitors of secretase enzymes that are required to cleave AβP from its precursor protein) prevented hypoxic augmentation of currents, as did inhibition of vesicular trafficking with bafilomycin A1. The enhancing effect of AβPs or CH were abolished following incubation with the monoclonal 3D6 antibody, raised against the extracellular N′ terminus of AβP. Immunolocalization and immunoprecipitation studies provided compelling evidence that AβPs physically associated with the α1C subunit, and this association was promoted by hypoxia. These data suggest an important role for AβPs in mediating the increase in Ca2+ channel activity following CH and show that AβPs act post‐transcriptionally to promote α1C 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.