Mitochondrial ROS Production Initiates Aβ_1-40-Mediated Up-Regulation of L-Type Ca²⁺ Channels during Chronic Hypoxia

Abstract

Exposure to chronic hypoxia (CH) initiates cellular responses designed to counteract this deleterious stimulus, providing a physiological response to low oxygen. However, long-term exposure to CH, such as that which occurs in cardiorespiratory diseases such as ischaemic stroke, can also have pathological consequences. In many cases, CH alters the transcription of genes encoding numerous proteins, secondary to accumulation of the transcriptional activator hypoxia inducible factor-1 (HIF-1) (Schofield and Ratcliffe, 2004). In contrast, we recently reported that hypoxic regulation of the plasma membrane expression of L-type Ca²⁺ channel α_1c subunits occurred in a post-transcriptional manner due to the trafficking of these subunits towards, and / or their retention within, the plasma membrane (Scragg et al., 2004). This process involved the altered production of amyloid β peptides (A Ps), since it was inhibited by selective inhibitors of the secretases involved in the production of these peptides, and mimicked by exogenous AβP. This regulation of the functional membrane expression of a voltage-gated Ca²⁺ channel may contribute to the Ca²⁺ dyshomeostasis seen in Alzheimer’s disease, a prevalent disorder in which hypoxia / ischaemia is a predisposing factor (Moroney et al., 1996).