Hydrogen peroxide inhibits gap junctional intercellular communication in glutathione sufficient but not glutathione deficient cells

Upham, Brad L.

doi:10.1093/carcin/18.1.37

Cited by 134 publications

(94 citation statements)

References 20 publications

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“…MK-801 antagonism of NMDA glutamate receptors (40) and inhibition of NOS have been shown to alter HBO 2 -induced seizure activity (25,60,70,227), and the actions of O 2 have been shown to decrease inhibitory (GABAergic) synaptic conductance (48). Gap junctional conductance through electrical synapses is also reduced by increased production of ROS (143,212), but the effects of HBO 2 on electrical coupling in mammalian neurons have not been investigated (56,98). This will be important to determine, however, because recent research has shown that CO 2 /H ϩ -chemosensitive neurons, which are coupled via gap junctions (56,57,98,190), are highly sensitive to HBO 2 and other chemical oxidants (152).…”

Section: Cellular Mechanism: O 2 -Induced Free Radicalsmentioning

confidence: 99%

Neuronal sensitivity to hyperoxia, hypercapnia, and inert gases at hyperbaric pressures

Dean¹,

Mulkey²,

Garcia³

et al. 2003

Journal of Applied Physiology

175

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III. Neuronal sensitivity to hyperoxia, hypercapnia, and inert gases at hyperbaric pressures. J Appl Physiol 95: 883-909, 2003; 10.1152/japplphysiol.00920.2002.-As ambient pressure increases, hydrostatic compression of the central nervous system, combined with increasing levels of inspired PO 2, PCO2, and N2 partial pressure, has deleterious effects on neuronal function, resulting in O 2 toxicity, CO2 toxicity, N2 narcosis, and high-pressure nervous syndrome. The cellular mechanisms responsible for each disorder have been difficult to study by using classic in vitro electrophysiological methods, due to the physical barrier imposed by the sealed pressure chamber and mechanical disturbances during tissue compression. Improved chamber designs and methods have made such experiments feasible in mammalian neurons, especially at ambient pressures Ͻ5 atmospheres absolute (ATA). Here we summarize these methods, the physiologically relevant test pressures, potential research applications, and results of previous research, focusing on the significance of electrophysiological studies at Ͻ5 ATA. Intracellular recordings and tissue PO 2 measurements in slices of rat brain demonstrate how to differentiate the neuronal effects of increased gas pressures from pressure per se. Examples also highlight the use of hyperoxia (Յ3 ATA O 2) as a model for studying the cellular mechanisms of oxidative stress in the mammalian central nervous system. anesthesia; carbon dioxide toxicity; free radicals; high-pressure nervous syndrome; membrane potential; nitrogen narcosis; oxidative stress; oxygen toxicity; polarographic oxygen electrode MOST HUMANS ARE PHYSIOLOGICALLY adapted to live and work near sea level, where ambient pressure is ϳ1 atmosphere absolute (ATA).1 Nonetheless, we exploit a continuum of barometric pressure (PB) ranging from the near vacuum of outer space, which we survive during Space Shuttle extravehicular activity by wearing a 4.3 lb./in.2 absolute (psia) pressure suit (30,300 ft. pressure equivalent, 0.29 ATA) (120, 220), down to the summit of Mt. Everest at 29,029 ft., where PB is 0.31 ATA (221), to ocean depths as great as 2,300 ft. of sea water (fsw), where PB increases to ϳ70 ATA (18). These situations are the pressure extremes of our inhabitable environment, which only relatively few highly trained individuals have ever occupied.Military personnel, medical personnel, and other humans, however, frequently encounter levels of hyperbaric pressure (i.e., Ͼ1 ATA) of lesser degrees in their normal work environments. Examples of moderate hyperbaric environments (e.g., Ͻ5 ATA) include the following: patients and medical attendants undergoing hyperbaric O 2 therapy (HBOT) (38,203); diving with an underwater breathing apparatus for recreational, professional (oil and salvage companies), and combat purposes (89); simulated dry and wet dives for hyperbaric research and dive training (217); and working in the compressed atmosphere of a subterranean environment (117). Abnormal work environments resulting from catastrophic accident...

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Section: Cellular Mechanism: O 2 -Induced Free Radicalsmentioning

confidence: 99%

Neuronal sensitivity to hyperoxia, hypercapnia, and inert gases at hyperbaric pressures

Dean¹,

Mulkey²,

Garcia³

et al. 2003

Journal of Applied Physiology

175

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“…Some of the earliest evidence of oxidative stress in gap junction function are (a) oxidative-dependent hepatotoxic levels of carbon tetrachloride reversibly block GJIC between rat hepatocytes (81a); (b) antioxidants prevent tumor promoter-induced inhibition of GJIC in mouse hepatocytes (80a); (c) paraquat-generated ROS inhibit GJIC in mouse hepatocytes. More recently, we reported that hydrogen peroxide inhibited GJIC in a dose-dependent fashion (103 Glutathione (GSH) in its reduced form is the major reductant of H 2 O 2 in mammalian cells, and the depletion of this antioxidant commonly results in greater oxidative damage of macromolecules. This two-electron reduction of H 2 O 2 by GSH to H 2 O is catalyzed by glutathione peroxidase, and clearly serves as a protective role against peroxide-dependent oxidative injury.…”

Section: Oxidative Control Of Gap Junctionsmentioning

confidence: 99%

“…This two-electron reduction of H 2 O 2 by GSH to H 2 O is catalyzed by glutathione peroxidase, and clearly serves as a protective role against peroxide-dependent oxidative injury. A previous report determined the effect of depleting GSH on H 2 O 2 -dependent regulation of GJIC in a rat liver epithelial cell line (103). GSH depletion in this study was achieved by either the conjugation of GSH with diethylmaleate (DEM) or by inhibiting ␥-glutamylcysteine synthetase, which catalyzes the rate-limiting step of the biosynthesis of GSH, with buthionine sulfoximine (BSO).…”

Section: Oxidative Control Of Gap Junctionsmentioning

confidence: 99%

Oxidative-Dependent Integration of Signal Transduction with Intercellular Gap Junctional Communication in the Control of Gene Expression

Upham

Trosko

2009

Antioxidants & Redox Signaling

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Research on oxidative stress focused primarily on determining how reactive oxygen species (ROS) damage cells by indiscriminate reactions with their macromolecular machinery, particularly lipids, proteins, and DNA. However, many chronic diseases are not always a consequence of tissue necrosis, DNA, or protein damage, but rather to altered gene expression. Gene expression is highly regulated by the coordination of cell signaling systems that maintain tissue homeostasis. Therefore, much research has shifted to the understanding of how ROS reversibly control gene expression through cell signaling mechanisms. However, most research has focused on redox regulation of signal transduction within a cell, but we introduce a more comprehensive-systems biology approach to understanding oxidative signaling that includes gap junctional intercellular communication, which plays a role in coordinating gene expression between cells of a tissue needed to maintain tissue homeostasis. We propose a hypothesis that gap junctions are critical in modulating the levels of second messengers, such as low molecular weight reactive oxygen, needed in the transduction of an external signal to the nucleus in the expression of genes. Thus, any comprehensive-systems biology approach to understanding oxidative signaling must also include gap junctions, in which aberrant gap junctions have been clearly implicated in many human diseases. Antioxid. Redox Signal. 11, 297-307. 297Oxidative Damage vs. Oxidative Signaling O XIDATIVE STRESS HAS LONG BEEN AFFILIATED with acute and chronic human diseases, and was believed to be primarily a consequence of indiscriminate, cumulative damage to proteins, lipids, and DNA from the vigorous production of reactive oxygen species (ROS) that overwhelm the cell's antioxidant defense system. However, pathological causes of many chronic diseases, particularly cancer, have also been linked with noncytotoxic nongenotoxic events, and the role of ROS and antioxidants in human diseases must also address epigenetic events (10,15,29,76,99).Oxygen was first implicated in cancer as far back as the 1920s by Otto Warburg (111). Initially his theory of altered oxidative metabolism fell mostly on deaf ears. However, recently there has been a renewed interest in how cancer cells shift their energy production from oxidative phosphorylation to anaerobic glycolysis, the "Warburg Effect," that is now considered a fundamental property of cancer cells and not just a consequence of malignant cell transformation (3,54,116). In contrast to this role of low oxygen tensions in cancer, the discovery of superoxide dismutase in 1968 by McCord and Fridovich (70) led to an explosion of research on the role of reactive oxygen, a product of high oxygen tensions, in the pathologies of biological organisms, and has been specifically connected with not only cancer but also many other human diseases (1, 41). For many years, research in oxidative stress at high oxygen tensions focused primarily on determining the mechanisms by which ROS damage cel...

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“…ROS have been associated with hormone stimulation (207,264) and specific gene activation (151,187,188) and can interact with signal transduction pathways (134, 223). Related to this point, glutathione has also been implicated in H 2 O 2 -mediated closure of gap junctions (129,273,308). H 2 O 2 -mediated closure of gap junctions also requires tyrosine kinase activity (126).…”

Section: Stressing Out the Neighborsmentioning

confidence: 99%

“…H 2 O 2 -mediated closure of gap junctions also requires tyrosine kinase activity (126). This was mediated by Cx43 hyperphosphorylation (127), was inhibited by glutathione depletion (273,308), and was not abrogated by free radical scavengers. Given these findings, it seems likely that the glutathione requirement observed for attenuating gap junctional communication may reflect a redox sensor activity as opposed to an antioxidant activity (190).…”

Section: Stressing Out the Neighborsmentioning

confidence: 99%

Sharing signals: connecting lung epithelial cells with gap junction channels

Koval

2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Gap junction channels enable the direct flow of signaling molecules and metabolites between cells. Alveolar epithelial cells show great variability in the expression of gap junction proteins (connexins) as a function of cell phenotype and cell state. Differential connexin expression and control by alveolar epithelial cells have the potential to enable these cells to regulate the extent of intercellular coupling in response to cell stress and to regulate surfactant secretion. However, defining the precise signals transmitted through gap junction channels and the cross talk between gap junctions and other signaling pathways has proven difficult. Insights from what is known about roles for gap junctions in other systems in the context of the connexin expression pattern by lung cells can be used to predict potential roles for gap junctional communication between alveolar epithelial cells.

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Hydrogen peroxide inhibits gap junctional intercellular communication in glutathione sufficient but not glutathione deficient cells

Cited by 134 publications

References 20 publications

Neuronal sensitivity to hyperoxia, hypercapnia, and inert gases at hyperbaric pressures

Neuronal sensitivity to hyperoxia, hypercapnia, and inert gases at hyperbaric pressures

Oxidative-Dependent Integration of Signal Transduction with Intercellular Gap Junctional Communication in the Control of Gene Expression

Sharing signals: connecting lung epithelial cells with gap junction channels

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