Researchers have speculated as to the molecular basis of O(2) sensing for decades. In more recent years, since the discovery of ion channels as identified effectors for O(2) sensing pathways, research has focussed on possible pathways coupling a reduction in hypoxia to altered ion channel activity. The most extensively studied systems are the K(+) channels which are inhibited by hypoxia in chemoreceptor tissues (carotid and neuroepithelial bodies). In this review, we consider the evidence supporting the involvement of well defined enzymes in mediating the regulation of K(+) channels by hypoxia. Specifically, we focus on the roles proposed for three enzyme systems; NADPH oxidase, heme oxygenase and AMP activated protein kinase. These systems differ in that the former two utilise O(2) directly (to form superoxide in the case of NADPH oxidase, and as a co-factor in the degradation of heme to carbon monoxide, bilirubin and ferrous iron in the case of heme oxygenase), but the third responds to shifts in the AMP:ATP ratio, so responds to changes in O(2) levels more indirectly. We consider the evidence in favour of each of these systems, and highlight their differential importance in different systems and species. Whilst the evidence for each playing an important role in different tissues is strong, there is a clear need for further study, and current awareness indicates that no one specific cell type may rely on a single mechanism for O(2) sensing.
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