Point Mutations in the Transmembrane Region of the Clic1 Ion Channel Selectively Modify Its Biophysical Properties

Averaimo, Stefania; Abeti, Rosella; Savalli, Nicoletta; Brown, Louise J.; Curmi, Paul M. G.; Breit, Samuel N.; Mazzanti, Michele

doi:10.1371/journal.pone.0074523

Cited by 23 publications

(30 citation statements)

References 38 publications

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“…The presence or absence of a selectivity filter is yet to be verified by structure‐function studies. However, the impression is reinforced by the similarity of the selectivity pattern to that exhibited by CLIC1 (Averaimo et al., ). In a direct analysis of the channel pore vestibule of CLIC1, lysine 37 (Fig.…”

Section: Biophysical Properties Of Clicsmentioning

confidence: 98%

“…Reversal potential measurements and ion substitution experiments in planar lipid bilayers indicate that CLIC channels can conduct both anions and cations (Gururaja Rao et al., ; Singh & Ashley, , ). These channels indicate a preference for anions over larger cations in an ectopic expression system and in planar bilayers (Averaimo et al., ; Tulk, Kapadia, & Edwards, ; Valenzuela et al., ).…”

Section: Biophysical Properties Of Clicsmentioning

confidence: 99%

“…) changed the channel conductance. This was attributed to the removal of positively charged residues that in turn reduced the residence time for anions in the channel pore (Averaimo et al., ). In the same study, arginine 29 (Fig.…”

Section: Biophysical Properties Of Clicsmentioning

confidence: 99%

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Three Decades of Chloride Intracellular Channel Proteins: From Organelle to Organ Physiology

et al. 2018

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Intracellular organelles are membranous structures central for maintaining cellular physiology and the overall health of the cell. To maintain cellular function, intracellular organelles are required to tightly regulate their ionic homeostasis. Any imbalance in ionic concentrations can disrupt energy production (mitochondria), protein degradation (lysosomes), DNA replication (nucleus), or cellular signaling (endoplasmic reticulum). Ionic homeostasis is also important for volume regulation of intracellular organelles and is maintained by cation and anion channels as well as transporters. One of the major classes of ion channels predominantly localized to intracellular membranes is chloride intracellular channel proteins (CLICs). They are non-canonical ion channels with six homologs in mammals, existing as either soluble or integral membrane protein forms, with dual functions as enzymes and channels. Provided in this overview is a brief introduction to CLICs, and a summary of recent information on their localization, biophysical properties, and physiological roles. © 2018 by John Wiley & Sons, Inc.

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Section: Biophysical Properties Of Clicsmentioning

confidence: 98%

Section: Biophysical Properties Of Clicsmentioning

confidence: 99%

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Three Decades of Chloride Intracellular Channel Proteins: From Organelle to Organ Physiology

et al. 2018

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“…Following an increase in expression, CLIC1 will translocate to the membrane in a cytosolic oxidative state [16, 40, 41]; this phenomenon corresponds to a peak of ROS during G1-S transition [42, 43]. CLIC1 ablation impaired the capacity of phagosomal proteolysis and reduced ROS through its ion channel activity in CLIC1 −/− macrophages, and similarly, CLIC1 −/− mice were protected from K/BxN arthritis, both suggesting that CLIC1 is a suitable target for anti-inflammation [28].…”

Section: Discussionmentioning

confidence: 99%

CLIC1 Inhibition Attenuates Vascular Inflammation, Oxidative Stress, and Endothelial Injury

Zhu

et al. 2016

PLoS ONE

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Endothelial dysfunction, which includes endothelial oxidative damage and vascular inflammation, is a key initiating step in the pathogenesis of atherosclerosis (AS) and an independent risk factor for this disorder. Intracellular chloride channel 1 (CLIC1), a novel metamorphic protein, acts as a sensor of cell oxidation and is involved in inflammation. In this study, we hypothesize that CLIC1 plays an important role in AS. Apolipoprotein E-deficient mice were supplied with a normal diet or a high-fat and high-cholesterol diet for 8 weeks. Overexpressed CLIC1 was associated with the accelerated atherosclerotic plaque development, amplified oxidative stress, and in vivo release of inflammatory cytokines. We subsequently examined the underlying molecular mechanisms through in vitro experiments. Treatment of cultured human umbilical vein endothelial cells (HUVECs) with H2O2 induced endothelial oxidative damage and enhanced CLIC1 expression. Suppressing CLIC1 expression through gene knocked-out (CLIC1−/−) or using the specific inhibitor indanyloxyacetic acid-94 (IAA94) reduced ROS production, increased SOD enzyme activity, and significantly decreased MDA level. CLIC1−/− HUVECs exhibited significantly reduced expression of TNF-α and IL-1β as well as ICAM-1 and VCAM-1 at the protein levels. In addition, H2O2 promoted CLIC1 translocation to the cell membrane and insertion into lipid membranes, whereas IAA94 inhibited CLIC1 membrane translocation induced by H2O2. By contrast, the majority of CLIC1 did not aggregate on the cell membrane in normal HUVECs, and this finding is consistent with the changes in cytoplasmic chloride ion concentration. This study demonstrates for the first time that CLIC1 is overexpressed during AS development both in vitro and in vivo and can regulate the accumulation of inflammatory cytokines and production of oxidative stress. Our results also highlight that deregulation of endothelial functions may be associated with the membrane translocation of CLIC1 and active chloride-selective ion channels in endothelial cells.

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“…Arg29 and Lys37 in the putative transmembrane domain have been shown to play a role in ion channel function. Lys37 altered the single-channel conductance whereas Arg29 affected the open probability of a single-channel in response to variation in membrane potential (Averaimo et al 2013). Ionic conductance of CLIC1 and CLIC5 is regulated by actin (Singh et al 2007), but not for CLIC4.…”

Section: Anion Channels Of Inner Mitochondrial Membranesmentioning

confidence: 99%

Anion Channels of Mitochondria

Ponnalagu

Singh

2016

Handbook of Experimental Pharmacology

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Mitochondria are the “power house” of a cell continuously generating ATP to ensure its proper functioning. The constant production of ATP via oxidative phosphorylation demands a large electrochemical force that drives protons across the highly selective and low-permeable mitochondrial inner membrane. Besides the conventional role of generating ATP, mitochondria also play an active role in calcium signaling, generation of reactive oxygen species (ROS), stress responses, and regulation of cell-death pathways. Deficiencies in these functions result in several pathological disorders like aging, cancer, diabetes, neurodegenerative and cardiovascular diseases. A plethora of ion channels and transporters are present in the mitochondrial inner and outer membranes which work in concert to preserve the ionic equilibrium of a cell for the maintenance of cell integrity, in physiological as well as pathophysiological conditions. For, e.g., mitochondrial cation channels KATP and BKCa play a significant role in cardioprotection from ischemia–reperfusion injury. In addition to the cation channels, mitochondrial anion channels are equally essential, as they aid in maintaining electro-neutrality by regulating the cell volume and pH. This chapter focusses on the information on molecular identity, structure, function, and physiological relevance of mitochondrial chloride channels such as voltage dependent anion channels (VDACs), uncharacterized mitochondrial inner membrane anion channels (IMACs), chloride intracellular channels (CLIC) and the aspects of forthcoming chloride channels.

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Point Mutations in the Transmembrane Region of the Clic1 Ion Channel Selectively Modify Its Biophysical Properties

Cited by 23 publications

References 38 publications

Three Decades of Chloride Intracellular Channel Proteins: From Organelle to Organ Physiology

Three Decades of Chloride Intracellular Channel Proteins: From Organelle to Organ Physiology

CLIC1 Inhibition Attenuates Vascular Inflammation, Oxidative Stress, and Endothelial Injury

Anion Channels of Mitochondria

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