Voltage-Gated Proton Channels Find Their Dream Job Managing the Respiratory Burst in Phagocytes

DeCoursey, Thomas E.

doi:10.1152/physiol.00039.2009

Cited by 83 publications

(97 citation statements)

References 209 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because, in activated macrophages, most NADPH oxidase components assemble at the plasma membrane, and then the components produce O 2 − inside the phagosome or extracellularly, and most O 2 − is converted to H 2 O 2 by nonenzymatic dismutation. 44,45) As shown in Fig. 9, JA-4 cells were incubated with LPS+IFN-γ for 8 h, and then the cells were treated further with SOD or catalase for 12 h. However, none of these treatments influ- …”

Section: Effects Of the Addition Of Sod And Catalase On Ho-1mentioning

confidence: 99%

Nitric Oxide Is an Important Regulator of Heme Oxygenase-1 Expression in the Lipopolysaccharide and Interferon-γ-Treated Murine Macrophage-Like Cell Line J774.1/JA-4

et al. 2015

View full text Add to dashboard Cite

1,2) Macrophages use a wide variety of pattern recognition receptors including Toll-like receptors (TLRs) that bind to these agents.3,4) Such receptors recognize various microbial components. 5) Once TLRs sense the presence of invading pathogens, their engagement with them activates macrophages, which then produce and release various sets of effector molecules aimed at destroying the foreign agents. Reactive oxygen species (ROS), such as superoxide anion (O 2 − ), hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO), are their front line effector molecules.6-11) These highly diffusive products exert strong cytotoxic activities against micro-organisms and many neighboring cells, including against the macrophages themselves. However, macrophages and most of the aerobic host cells can protect themselves by enhancing the expression of heme oxygenase (HO). HO, a cellular antioxidant, is one of the key enzymes catalyzing the degradation of heme-containing molecules to biliverdin, free iron, and carbon monoxide.12,13) Three HO isozymes, including HO-1 (HSP32), HO-2, and HO-3, have been identified 14) ; although HO-3 may be a pseudo gene derived from HO-2 transcripts. 15)HO-1 is an inducible enzyme, whereas HO-2 is constitutive one.16) HO-1 is induced by various molecules and environmental factors, such as heme, radiation, cytokine, oxidative, and heat stresses. [17][18][19][20][21] Previous studies reported that lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, also induces the expression of both the HO-1 gene and its protein in macrophages.22-24) Exposure of HO-1-deficient mice to LPS leads to increased hepatocellular necrosis, increased splenic proinflammatory cytokine secretion, and higher mortality of septic shock when compared with wild-type animals. 25,26) These studies suggest that HO-1 plays an important role in reducing the deleterious increase in oxidative damage. Srisook et al. reported that both O 2 − and NO are related to HO-1 induction in macrophages by using an O 2 − generator and a NO donor. 27) However, it is not easy to study the role of O 2 − and NO separately in HO-1 induction in activated macrophages which produce both of these molecules simultaneously after LPS-treatment. Thus, among ROS, the important regulators of HO-1 in the activated macrophages have not been clear. The aim of the present work was to identify the regulator of HO-1 induction in activated macrophages. In this study, we sought to identify the regulator of HO-1 induction of the activated macrophages by using 2 types of macrophages, i.e., cells of the murine macrophage-like cell line J774.1/JA-4 and their LPS-resistant mutant, LPS1916. 7) This mutant cell line is characterized by a specific defect in the induction of ROS after LPS treatment. Our recent study reported that LPS1916 cells have the phenotype of mal-expression of CD14, a key molecule required for LPS-induced activation of cells, on the macrophage cell surface, leading to reduced responses to LPS. 28) Interestingly, this defect i...

show abstract

Section: Effects Of the Addition Of Sod And Catalase On Ho-1mentioning

confidence: 99%

Nitric Oxide Is an Important Regulator of Heme Oxygenase-1 Expression in the Lipopolysaccharide and Interferon-γ-Treated Murine Macrophage-Like Cell Line J774.1/JA-4

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Upon activation the soluble subunits of the NADPH oxidase complex are recruited to phagosomal membranes where they bind gp91phox resulting in the transfer of electrons across the wall of the phagocytic vacuole and the generation of superoxide in the lumen (Segal and Shatwell, 1997). The passage of electrons across the membrane results in a negatively charged lumen (Lamb et al, 2009), which is compensated by the influx of protons via the v-ATPase and the voltage-gated proton channel (Liu and Chu, 2006;DeCoursey, 2010).…”

Section: Introductionmentioning

confidence: 99%

Intracellular chloride channel protein CLIC1 regulates macrophage functions via modulation of phagosomal acidification

Jiang

Salao

et al. 2012

Journal of Cell Science

View full text Add to dashboard Cite

SummaryIntracellular chloride channel protein 1 (CLIC1) is a 241 amino acid protein of the glutathione S transferase fold family with redox-and pH-dependent membrane association and chloride ion channel activity. Whilst CLIC proteins are evolutionarily conserved in Metazoa, indicating an important role, little is known about their biology. CLIC1 was first cloned on the basis of increased expression in activated macrophages. We therefore examined its subcellular localisation in murine peritoneal macrophages by immunofluorescence confocal microscopy. In resting cells, CLIC1 is observed in punctate cytoplasmic structures that do not colocalise with markers for endosomes or secretory vesicles. However, when these macrophages phagocytose serum-opsonised zymosan, CLIC1 translocates onto the phagosomal membrane. Macrophages from CLIC1 2/2 mice display a defect in phagosome acidification as determined by imaging live cells phagocytosing zymosan tagged with the pH-sensitive fluorophore Oregon Green. This altered phagosomal acidification was not accompanied by a detectable impairment in phagosomal-lysosomal fusion. However, consistent with a defect in acidification, CLIC1 2/2 macrophages also displayed impaired phagosomal proteolytic capacity and reduced reactive oxygen species production. Further, CLIC12/2 mice were protected from development of serum transfer induced K/BxN arthritis. These data all point to an important role for CLIC1 in regulating macrophage function through its ion channel activity and suggest it is a suitable target for the development of anti-inflammatory drugs.

show abstract

“…Hv1 plays major roles in controlling B-cell proliferation, human sperm motility, and acid extrusion in lung epithelial cells (4,5), and it is involved in immunological processes, such as phagocytosis (1,6) and histamine secretion (7). Unlike other voltage-gated ion channels (VGICs), Hv1 is composed of two identical transmembrane (TM) subunits.…”

mentioning

confidence: 99%

On the role of water density fluctuations in the inhibition of a proton channel

Gianti

Delemotte

Klein

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hv1 is a transmembrane four-helix bundle that transports protons in a voltage-controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel's most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel.Hv1 | drug design | pore waters | binding site discovery | confined waters

show abstract

Voltage-Gated Proton Channels Find Their Dream Job Managing the Respiratory Burst in Phagocytes

Cited by 83 publications

References 209 publications

Nitric Oxide Is an Important Regulator of Heme Oxygenase-1 Expression in the Lipopolysaccharide and Interferon-γ-Treated Murine Macrophage-Like Cell Line J774.1/JA-4

Nitric Oxide Is an Important Regulator of Heme Oxygenase-1 Expression in the Lipopolysaccharide and Interferon-γ-Treated Murine Macrophage-Like Cell Line J774.1/JA-4

Intracellular chloride channel protein CLIC1 regulates macrophage functions via modulation of phagosomal acidification

On the role of water density fluctuations in the inhibition of a proton channel

Contact Info

Product

Resources

About