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J Physiol
2017 Nov 01;59521:6719-6733. doi: 10.1113/JP274795.
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Subunit-dependent oxidative stress sensitivity of LRRC8 volume-regulated anion channels.
Gradogna A
,
Gavazzo P
,
Boccaccio A
,
Pusch M
.
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KEY POINTS: Swelling-activated anion currents are modulated by oxidative conditions, but it is unknown if oxidation acts directly on the LRRC8 channel-forming proteins or on regulatory factors. We found that LRRC8A-LRRC8E heteromeric channels are dramatically activated by oxidation of intracellular cysteines, whereas LRRC8A-LRRC8C and LRRC8A-LRRC8D heteromers are inhibited by oxidation. Volume-regulated anion currents in Jurkat T lymphocytes were inhibited by oxidation, in agreement with a low expression of the LRRC8E subunit in these cells. Our results show that LRRC8 channel proteins are directly modulated by oxidation in a subunit-specific manner.
ABSTRACT: The volume-regulated anion channel (VRAC) is formed by heteromers of LRRC8 proteins containing the essential LRRC8A subunit and at least one among the LRRC8B-E subunits. Reactive oxygen species (ROS) play physiological and pathophysiological roles and VRAC channels are highly ROS sensitive. However, it is unclear if ROS act directly on the channels or on molecules involved in the activation pathway. We used fluorescently tagged LRRC8 proteins that yield large constitutive currents to test direct effects of oxidation. We found that 8A/8E heteromers are dramatically potentiated (more than 10-fold) by oxidation of intracellular cysteine residues by chloramine-T or tert-butyl hydroperoxide. Oxidation was, however, not necessary for hypotonicity-induced activation. In contrast, 8A/8C and 8A/8D heteromers were strongly inhibited by oxidation. Endogenous VRAC currents in Jurkat T lymphocytes were similarly inhibited by oxidation, in agreement with the finding that LRRC8C and LRRC8D subunits were more abundantly expressed than LRRC8E in Jurkat cells. Our results show that LRRC8 channels are directly modulated by oxidation in a subunit-dependent manner.
Abascal,
LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication.
2012, Pubmed
Abascal,
LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication.
2012,
Pubmed
Behe,
The LRRC8A Mediated "Swell Activated" Chloride Conductance Is Dispensable for Vacuolar Homeostasis in Neutrophils.
2017,
Pubmed
Belikov,
T cells and reactive oxygen species.
2015,
Pubmed
Browe,
Angiotensin II (AT1) receptors and NADPH oxidase regulate Cl- current elicited by beta1 integrin stretch in rabbit ventricular myocytes.
2004,
Pubmed
Cahalan,
Role of potassium and chloride channels in volume regulation by T lymphocytes.
1988,
Pubmed
Chen,
Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment.
2016,
Pubmed
Crutzen,
Does NAD(P)H oxidase-derived H2O2 participate in hypotonicity-induced insulin release by activating VRAC in β-cells?
2012,
Pubmed
Decoursey,
Voltage-gated proton channels and other proton transfer pathways.
2003,
Pubmed
Deng,
HIV protease inhibitors elicit volume-sensitive Cl- current in cardiac myocytes via mitochondrial ROS.
2010,
Pubmed
Duprat,
Pancreatic two P domain K+ channels TALK-1 and TALK-2 are activated by nitric oxide and reactive oxygen species.
2005,
Pubmed
,
Xenbase
Friard,
VRAC: unravelling the complexity of LRRC8 subunit regulation by oxidation.
2019,
Pubmed
Gaitán-Peñas,
Investigation of LRRC8-Mediated Volume-Regulated Anion Currents in Xenopus Oocytes.
2016,
Pubmed
,
Xenbase
Gradogna,
Cisplatin activates volume sensitive LRRC8 channel mediated currents in Xenopus oocytes.
2017,
Pubmed
,
Xenbase
Harrigan,
Activation of microglia with zymosan promotes excitatory amino acid release via volume-regulated anion channels: the role of NADPH oxidases.
2008,
Pubmed
Holm,
Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase.
2013,
Pubmed
Jentsch,
VRACs and other ion channels and transporters in the regulation of cell volume and beyond.
2016,
Pubmed
Kumar,
Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function.
2014,
Pubmed
Lambert,
Reactive oxygen species regulate swelling-induced taurine efflux in NIH3T3 mouse fibroblasts.
2003,
Pubmed
Le Gal,
Antioxidants can increase melanoma metastasis in mice.
2015,
Pubmed
Lepple-Wienhues,
The tyrosine kinase p56lck mediates activation of swelling-induced chloride channels in lymphocytes.
1998,
Pubmed
Lewis,
Chloride channels activated by osmotic stress in T lymphocytes.
1993,
Pubmed
Liu,
Bradykinin-induced astrocyte-neuron signalling: glutamate release is mediated by ROS-activated volume-sensitive outwardly rectifying anion channels.
2009,
Pubmed
Lutter,
Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels.
2017,
Pubmed
López-Otín,
The hallmarks of aging.
2013,
Pubmed
Muralidharan,
Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation.
2013,
Pubmed
Nilius,
Properties of volume-regulated anion channels in mammalian cells.
1997,
Pubmed
Nilius,
Activation of volume-regulated chloride currents by reduction of intracellular ionic strength in bovine endothelial cells.
1998,
Pubmed
Okada,
Pathophysiology and puzzles of the volume-sensitive outwardly rectifying anion channel.
2009,
Pubmed
Pedersen,
Biophysics and Physiology of the Volume-Regulated Anion Channel (VRAC)/Volume-Sensitive Outwardly Rectifying Anion Channel (VSOR).
2016,
Pubmed
Piskounova,
Oxidative stress inhibits distant metastasis by human melanoma cells.
2015,
Pubmed
Planells-Cases,
Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs.
2015,
Pubmed
Platt,
Leucine-rich repeat containing 8A (LRRC8A)-dependent volume-regulated anion channel activity is dispensable for T-cell development and function.
2017,
Pubmed
Qiu,
SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel.
2014,
Pubmed
Sawada,
A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans.
2003,
Pubmed
Schwab,
Role of ion channels and transporters in cell migration.
2012,
Pubmed
Shen,
Activation of volume-sensitive outwardly rectifying chloride channel by ROS contributes to ER stress and cardiac contractile dysfunction: involvement of CHOP through Wnt.
2014,
Pubmed
Shimizu,
A role of reactive oxygen species in apoptotic activation of volume-sensitive Cl(-) channel.
2004,
Pubmed
Syeda,
LRRC8 Proteins Form Volume-Regulated Anion Channels that Sense Ionic Strength.
2016,
Pubmed
Ullrich,
Inactivation and Anion Selectivity of Volume-regulated Anion Channels (VRACs) Depend on C-terminal Residues of the First Extracellular Loop.
2016,
Pubmed
Varela,
Activation of H2O2-induced VSOR Cl- currents in HTC cells require phospholipase Cgamma1 phosphorylation and Ca2+ mobilisation.
2007,
Pubmed
Varela,
NAD(P)H oxidase-derived H(2)O(2) signals chloride channel activation in cell volume regulation and cell proliferation.
2004,
Pubmed
Voss,
Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC.
2014,
Pubmed
Wang,
Volume-sensitive outwardly rectifying chloride channel blockers protect against high glucose-induced apoptosis of cardiomyocytes via autophagy activation.
2017,
Pubmed
Wang,
Chloride channel inhibition prevents ROS-dependent apoptosis induced by ischemia-reperfusion in mouse cardiomyocytes.
2005,
Pubmed
Wang,
The volume-regulated anion channel (LRRC8) in nodose neurons is sensitive to acidic pH.
2017,
Pubmed
Xia,
Activation of volume-sensitive Cl- channel mediates autophagy-related cell death in myocardial ischaemia/reperfusion injury.
2016,
Pubmed