Tissue oxygen sensor function of NADPH oxidase isoforms, an unusual cytochrome aa3 and reactive oxygen species (original) (raw)
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The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases
Cardiovascular …, 2006
Current concepts of cellular oxygen-sensing include an isoform of the neutrophil NADPH oxidase, different electron carrier units of the mitochondrial electron transport chain (ETC), heme oxygenase-2 (HO-2), and a subfamily of 2-oxoglutarate dependent dioxygenases termed HIF (hypoxia inducible factor) prolyl hydroxylases (PHDs) and HIF asparagyl hydroxylase FIH-1 (factor-inhibiting HIF). Different oxygen sensitivities, cell-specific distribution and subcellular localization of specific oxygen-sensing cascades involving reactive oxygen species (ROS) as second messengers may help to tailor various adaptive responses according to differences in tissue oxygen availability. Herein, we propose an integrated model for these various oxygen-sensing mechanisms that very efficiently regulate HIF-a activity and plasma membrane potassium-channel (PMPC) conductivity.
NADPH oxidase: a universal oxygen sensor?
Free Radical Biology and Medicine, 2000
NADPH oxidase is classically regarded as a key enzyme of neutrophils, where it is involved in the pathogenic production of reactive oxygen species. However, NADPH oxidase-like enzymes have recently been identified in non-neutrophil cells, supporting a separate role for NADPH-oxidase derived oxygen species in oxygen sensitive processes. This article reviews the current literature surrounding the potential role of NADPH oxidase in the oxygen sensing processes which underlie hypoxic pulmonary vasoconstriction, systemic vascular smooth muscle proliferation, carotid and airways chemoreceptor activation, erythropoietin gene expression, and oxytropic responses of plant cells.
Enzyme-Linked Oxygen Sensing by Potassium Channels
Annals of the New York Academy of Sciences, 2009
The ability of ion channels to respond to an acute perturbation in oxygen tension is a widespread phenomenon, which encompasses many of the major ion channel families. Integral to the ability of several ion channels to respond to acute hypoxic challenge is modulation by upstream enzymatic reactions, suggesting that many ion channels sense oxygen via enzyme-linked processes. Several enzyme-linked oxygen sensing systems have been proposed, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent production of hydrogen peroxide, hemoxygenase-dependent generation of carbon monoxide, adenosine monophosphate (AMP) kinase-dependent channel phosphorylation, and src-Lck protein tyrosine kinase, via a currently undetermined mechanism. Each of these enzymes has been shown to endow specific ion channels with the ability to respond to changes in oxygen, with hypoxia exclusively evoking channel inhibition. This article reviews these proposed mechanisms and presents new insights into how one system, hemeoxygenase-2, confers oxygen sensitivity to large conductance, voltage-and calcium-activated potassium channels.
Significance of ROS in oxygen sensing in cell systems with sensitivity to physiological hypoxia
Respiratory Physiology & Neurobiology, 2002
Reactive oxygen species (ROS) are oxygen-containing molecular entities which are more potent and effective oxidizing agents than is molecular oxygen itself. With the exception of phagocytic cells, where ROS play an important physiological role in defense reactions, ROS have classically been considered undesirable byproducts of cell metabolism, existing several cellular mechanisms aimed to dispose them. Recently, however, ROS have been considered important intracellular signaling molecules, which may act as mediators or second messengers in many cell functions. This is the proposed role for ROS in oxygen sensing in systems, such as carotid body chemoreceptor cells, pulmonary artery smooth muscle cells, and erythropoietin-producing cells. These unique cells comprise essential parts of homeostatic loops directed to maintain oxygen levels in multicellular organisms in situations of hypoxia. The present article examines the possible significance of ROS in these three cell systems, and proposes a set of criteria that ROS should satisfy for their consideration as mediators in hypoxic transduction cascades. In none of the three cell types do ROS satisfy these criteria, and thus it appears that alternative mechanisms are responsible for the transduction cascades linking hypoxia to the release of neurotransmitters in chemoreceptor cells, contraction in pulmonary artery smooth muscle cells and erythropoietin secretion in erythropoietin producing cells.
Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation
Cell Metabolism, 2005
low oxygen levels (hypoxia). One such response is stabilization of the protein HIF-1α, a component of the transcription factor HIF-1. Here we show that a small interfering RNA (siRNA) against the Rieske iron-sulfur protein of mitochondrial complex III prevents the hypoxic stabilization of HIF-1α protein. Fibroblasts from a patient with Leigh's syndrome, which display residual levels of electron transport activity and are incompetent in oxidative phosphorylation, stabilize HIF-1α during hypoxia. The expression of glutathione peroxidase or catalase, but not superoxide dismutase 1 or 2, prevents the hypoxic stabilization of HIF-1α. These findings provide genetic evidence that oxygen sensing is dependent on mitochondrial-generated reactive oxygen species (ROS) but independent of oxidative phosphorylation.
European Journal of Biochemistry, 2000
Molecular oxygen (O 2 ) regulates the expression of a variety of genes. Several of the proteins that respond to changes in oxygen concentration have been identified in a variety of cell lines. We extend these previous studies by analyzing the effect of oxygen on the entire protein expression profile of an intact organ using high-resolution two-dimensional gel electrophoresis. To this end, we used an isolated, in vitro perfused organ preparation to produce two groups of rat livers perfused with high (95% O 2 , 5% CO 2 ) or low (95% N 2 , 5% CO 2 ) oxygen concentrations. Using two-dimensional gel electrophoresis we compared the protein expression profiles of both groups of livers. Computer analysis of the files obtained after laser densitometry of the two-dimensional gels revealed two spots that were strongly up-regulated in high PO 2 perfused livers compared with low PO 2 perfused livers. These spots were analyzed by peptide mass fingerprinting analysis. These spots were identified as arginase 1 (liver-type arginase; EC 3.5.3.1) and mitochondrial enoyl-CoA hydratase 1 (EC 4.2.1.17). The possible role of these proteins in its new context of oxygen availability is discussed.
Oxygen sensing by ion channels
Kidney International, 1997
1. Kidney Int. 1997 Feb;51(2):454-61. Oxygen sensing by ion channels. López-Barneo J, Ortega-Sáenz P, Molina A, Franco-Obregón A, Ureña J, Castellano A. Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Facultad de Medicina, Spain. ...
Proceedings of The National Academy of Sciences, 1996
Pulmonary neuroepithelial bodies (NEB) are widely distributed throughout the airway mucosa of human and animal lungs. Based on the observation that NEB cells have a candidate oxygen sensor enzyme complex (NADPH oxidase) and an oxygen-sensitive K ؉ current, it has been suggested that NEB may function as airway chemoreceptors. Here we report that mRNAs for both the hydrogen peroxide sensitive voltage gated potassium channel subunit (KH 2 O 2 ) KV3.3a and membrane components of NADPH oxidase (gp91 phox and p22 phox ) are coexpressed in the NEB cells of fetal rabbit and neonatal human lungs. Using a microfluorometry and dihydrorhodamine 123 as a probe to assess H 2 O 2 generation, NEB cells exhibited oxidase activity under basal conditions. The oxidase in NEB cells was significantly stimulated by exposure to phorbol esther (0.1 M) and inhibited by diphenyliodonium (5 M). Studies using wholecell voltage clamp showed that the K ؉ current of cultured fetal rabbit NEB cells exhibited inactivating properties similar to KV3.3a transcripts expressed in Xenopus oocyte model. Exposure of NEB cells to hydrogen peroxide (H 2 O 2 , the dismuted byproduct of the oxidase) under normoxia resulted in an increase of the outward K ؉ current indicating that H 2 O 2 could be the transmitter modulating the O 2 -sensitive K ؉ channel. Expressed mRNAs or orresponding protein products for the NADPH oxidase membrane cytochrome b as well as mRNA encoding KV3.3a were identified in small cell lung carcinoma cell lines. The studies presented here provide strong evidence for an oxidase-O 2 sensitive potassium channel molecular complex operating as an O 2 sensor in NEB cells, which function as chemoreceptors in airways and in NEB related tumors. Such a complex may represent an evolutionary conserved biochemical link for a membrane bound O 2 -signaling mechanism proposed for other cells and life forms.