signalling pathways in acute oxygen sensing, no. 272 - novartis foundation
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signalling pathways in acute oxygen sensing, no. 272
novartis foundation
Synopsis "signalling pathways in acute oxygen sensing, no. 272"
oxygen sensing is a key physiological function of many tissues, but the identity of the sensor, the signalling pathways linking the sensor to the effector and the endpoint effector mechanisms are all subjects of controversy. various mechanisms have been proposed to act as oxygen sensors, including activities within mitochondria, nad(p)h oxidases, cytochrome p450 enzymes, other enzymes and ion channels. recently, there has been a resurgence of interest in the role of mitochondria, based partly on the ability of mitochondrial inhibitors to mimic hypoxia, although this is questioned in some quarters. there is, however, little consensus concerning mechanisms. whilst some favour the view that the primary signalling event is a reduction in cell redox state and the number of reactive oxygen species (ros) owing to general inhibition of the electron transport chain, others support a key role for complex iii of the electron transport chain and an increase in ros generation. yet others do not support a role for ros at all, and a recent report has cast doubts on any role for the electron transport chain in oxygen sensing in the carotid body. moreover, in tissues such as neuroepithelia, an nad(p)h oxidase may act as the oxygen sensor. there are also key conceptual problems concerning the ability of mitochondria to respond to physiological hypoxia, as some reports suggest that mitochondrial respiration is inhibited only when hypoxia is very severe. there is similar diversity of opinion concerning the endpoint effector(s). there is considerable support for a central role for potassium channel inhibition, followed by depolarization and calcium entry via l-type channels. however, the molecular identity of the channels involved is contentious. an essential role for potassium channel inhibition has been questioned, particularly in hypoxic pulmonary vasoconstriction, where it has been suggested that release of ca2+ from intracellular stores or capacitative ca2+ entry and other voltage-independent pathways may be more important. moreover, there is also good evidence for an endothelium-dependent ca2+ sensitizing pathway involving rho and possibly other kinases. whilst some of these differences can be attributed to variation between tissues, many must be related to differences in interpretation or methodology. the aim of this book is to bring together contributions from experts in the field of acute oxygen sensing working on different tissues to address these controversies and their possible origins, and to develop approaches whereby these controversies might be resolved.
