Hypoxic augmentation of Ca2+ channel currents requires a functional electron transport chain.

The incidence of Alzheimer disease is increased following ischemic episodes, and we previously demonstrated that following chronic hypoxia (CH), amyloid beta (Abeta) peptide-mediated increases in voltage-gated L-type Ca(2+) channel activity contribute to the Ca(2+) dyshomeostasis seen in Alzheimer disease. Because in certain cell types mitochondria are responsible for detecting altered O(2) levels we examined the role of mitochondrial oxidant production in the regulation of recombinant Ca(2+) channel alpha(1C) subunits during CH and exposure to Abeta-(1-40). In wild-type (rho(+)) HEK 293 cells expressing recombinant L-type alpha(1C) subunits, Ca(2+) currents were enhanced by prolonged (24 h) exposure to either CH (6% O(2)) or Abeta-(1-40) (50 nm).

H2O2 regulates recombinant Ca2+ channel alpha1C subunits but does not mediate their sensitivity to acute hypoxia.

Acute hypoxic inhibition of the pore-forming alpha(1C) subunit of the L-type Ca(2+) channel mediates hypoxic arterial vasodilatation, a physiological response which matches tissue O(2) demand and supply in the systemic vasculature. In numerous O(2)-sensing cell types, reactive O(2) species (ROS) have been proposed as mediators linking lowered O(2) levels with the appropriate cellular response. In this study, we examined the roles of H(2)O(2) and NADPH oxidase as mediators of hypoxic inhibition of recombinant alpha(1C) subunits.