scholarly journals The Plasmodial Surface Anion Channel Is Functionally Conserved in Divergent Malaria Parasites

2005 ◽  
Vol 4 (12) ◽  
pp. 2153-2159 ◽  
Author(s):  
Godfrey Lisk ◽  
Sanjay A. Desai
Keyword(s):  
Copy Number ◽  
Plasmodium Knowlesi ◽  
Osmotic Fragility ◽  
Anion Channel ◽  
Parasite Growth ◽  
Anion Channels ◽  
Malaria Parasites ◽  
Voltage Dependent ◽  
Host Cell Surface ◽  
Exposed Location

ABSTRACT The plasmodial surface anion channel (PSAC), a novel ion channel induced on human erythrocytes infected with Plasmodium falciparum, mediates increased permeability to nutrients and presumably supports intracellular parasite growth. Isotope flux studies indicate that other malaria parasites also increase the permeability of their host erythrocytes, but the precise mechanisms are unknown. Channels similar to PSAC or alternative mechanisms, such as the upregulation of endogenous host transporters, might fulfill parasite nutrient demands. Here we evaluated these possibilities with rhesus monkey erythrocytes infected with Plasmodium knowlesi, a parasite phylogenetically distant from P. falciparum. Tracer flux and osmotic fragility studies revealed dramatically increased permeabilities paralleling changes seen after P. falciparum infection. Patch-clamp of P. knowlesi-infected rhesus erythrocytes revealed an anion channel with striking similarities to PSAC: its conductance, voltage-dependent gating, pharmacology, selectivity, and copy number per infected cell were nearly identical. Our findings implicate a family of unusual anion channels highly conserved on erythrocytes infected with various malaria parasites. Together with PSAC's exposed location on the host cell surface and its central role in transport changes after infection, this conservation supports development of antimalarial drugs against the PSAC family.

scholarly journals Voltage-dependent block of endothelial volume-regulated anion channels by calix[4]arenes

1998 ◽  
Vol 275 (3) ◽  
pp. C646-C652 ◽  
Author(s):  
Guy Droogmans ◽  
Jean Prenen ◽  
Jan Eggermont ◽  
Thomas Voets ◽  
Bernd Nilius
Keyword(s):  
Open Channel ◽  
Single Channel ◽  
Anion Channel ◽  
Anion Channels ◽  
Channel Conductance ◽  
Open Channel Block ◽  
Maximum Inhibition ◽  
Voltage Dependent ◽  
A Site ◽  
Maximal Block

We have studied the effects of calix[4]arenes on the volume-regulated anion channel (VRAC) currents in cultured calf pulmonary artery endothelial cells. TS- and TS-TM-calix[4]arenes induced a fast inhibition at positive potentials but were ineffective at negative potentials. Maximal block occurred at potentials between 30 and 50 mV. Lowering extracellular pH enhanced the block and shifted the maximum inhibition to more negative potentials. Current inhibition was also accompanied by an increased current noise. From the analysis of the calix[4]arene-induced noise, we obtained a single-channel conductance of 9.3 ± 2.1 pS ( n = 9) at +30 mV. The voltage- and time-dependent block were described using a model in which calix[4]arenes bind to a site at an electrical distance of 0.25 inside the channel with an affinity of 220 μM at 0 mV. Binding occludes VRAC at moderately positive potentials, but calix[4]arenes permeate the channel at more positive potentials. In conclusion, our data suggest an open-channel block of VRAC by calix[4]arenes that also depends on the protonation of the binding site within the pore.

Endothelium modulates anion channel-dependent aortic contractions to iodide

2000 ◽  
Vol 278 (5) ◽  
pp. H1527-H1536 ◽  
Author(s):  
Fred S. Lamb ◽  
Thomas J. Barna
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Membrane Potential ◽  
Anion Channel ◽  
Anion Channels ◽  
Anion Substitution ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Channel Dependent ◽  
Cytochrome P 450

Anion currents contribute to vascular smooth muscle (VSM) membrane potential. The substitution of extracellular chloride (Cl) with iodide (I) or bromide (Br) initially inhibited and then potentiated isometric contractile responses of rat aortic rings to norepinephrine. Anion substitution alone produced a small relaxation, which occurred despite a lack of active tone and minimal subsequent contraction of endothelium-intact rings (4.2 ± 1.2% of the response to 90 mM KCl). Endothelium-denuded rings underwent a similar initial relaxation but then contracted vigorously (I > Br). Responses to 130 mM I (93.7 ± 1.9% of 90 mM KCl) were inhibited by nifedipine (10− 6 M), niflumic acid (10− 5 M), tamoxifen (10− 5 M), DIDS (10− 4 M), and[Formula: see text]-free buffer (HEPES 10 mM) but not by bumetanide (10− 5 M). Intact rings treated with N ω-nitro-l-arginine (10− 4 M) responded weakly to I (15.5 ± 2.1% of 90 mM KCl), whereas hemoglobin (10− 5 M), indomethacin (10− 6 M), 17-octadecynoic acid (10− 5 M), and 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10− 6 M) all failed to augment the response of intact rings to I. We hypothesize that VSM takes up I primarily via an anion exchanger. Subsequent I efflux through anion channels having a selectivity of I > Br > Cl produces depolarization. In endothelium-denuded or agonist-stimulated vessels, this current is sufficient to activate voltage-dependent calcium channels and cause contraction. Neither nitric oxide nor prostaglandins are the primary endothelial modulator of these anion channels. If they are regulated by an endothelium-dependent hyperpolarizing factor it is not a cytochrome P-450 metabolite.

scholarly journals Voltage-dependent anion channels mediated apoptosis in refractory epilepsy

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 745-753
Author(s):  
Yan Zhao ◽  
Wen-Jing Jiang ◽  
Lin Ma ◽  
Yan Lin ◽  
Xing-Bang Wang
Keyword(s):  
Cell Death ◽  
Essential Role ◽  
Refractory Epilepsy ◽  
Apoptotic Cell ◽  
Anion Channel ◽  
Anion Channels ◽  
Voltage Dependent Anion Channel ◽  
Caspase 9 ◽  
Voltage Dependent

AbstractThe purpose of this study was to investigate the role of voltage-dependent anion channel (VDAC) in mitochondria-mediated apoptosis of neurons in refractory epilepsy. Western blot analyses were carried out to detect the changes in cytochrome C, caspase 9, Bax, and Bcl-2. TUNEL assays were also carried out to investigate cell apoptosis under the upregulation and downregulation of VDAC1 with or without Bax or Bcl-2. VDAC1 induced Bax, Bcl-2, and caspase 9, increasing the release of cytochrome C. VDAC1 played an essential role in the apoptotic cell death of refractory epilepsy. It is concluded that VDAC1 plays an important role in refractory epilepsy and could be a possible therapeutic target of anti-epileptic drugs. The current study provides a new understanding of the possible mechanisms of refractory epilepsy.

scholarly journals Expression of voltage-dependent anion channels in endometrial cancer and its potential prognostic significance

Tumor Biology ◽  
2020 ◽  
Vol 42 (8) ◽  
pp. 101042832095105
Author(s):  
Paweł Jóźwiak ◽  
Piotr Ciesielski ◽  
Ewa Forma ◽  
Karolina Kozal ◽  
Katarzyna Wójcik-Krowiranda ◽  
...  
Keyword(s):  
Overall Survival ◽  
Endometrial Cancer ◽  
Protein Level ◽  
Prognostic Significance ◽  
Anion Channel ◽  
Mrna Levels ◽  
Anion Channels ◽  
Voltage Dependent Anion Channel ◽  
Poor Overall Survival ◽  
Voltage Dependent

The exchange of metabolites between mitochondria and cytosol occurs through pores formed by voltage-dependent anion channel proteins. Voltage-dependent anion channels appear to be master regulators of mitochondrial bioenergetics and the intracellular flow of energy. Deregulation of voltage-dependent anion channels expression is thought to be related to mitochondrial dysfunction in cancer. The aim of this study was to investigate the mRNA and protein expression levels of VDAC1, VDAC2, and VDAC3 in relation to clinicopathological characteristics of endometrial cancer as well as the prognostic significance of voltage-dependent anion channels expression for overall survival. VDAC1 and VDAC3 expressions were significantly higher in cancer compared to normal tissues. Kaplan–Meier analysis indicated that high expression of all VDAC genes or high VDAC2 protein level predicted poor overall survival. Multivariate analysis identified the VDAC1 and VDAC2 mRNA levels as well as VDAC2 protein level as independent prognostic factors. Our results suggest that increased expression of voltage-dependent anion channels correlates with tumor progression and may serve as a potential prognostic biomarker in endometrial cancer.

scholarly journals Channel-like slippage modes in the human anion/proton exchanger ClC-4

2009 ◽  
Vol 133 (5) ◽  
pp. 485-496 ◽  
Author(s):  
Alexi K. Alekov ◽  
Christoph Fahlke
Keyword(s):  
Mammalian Cells ◽  
Stable Distribution ◽  
Noise Analysis ◽  
Anion Channel ◽  
Proton Exchange ◽  
Anion Channels ◽  
Mode Behavior ◽  
Voltage Dependent ◽  
Transport Modes ◽  
Active Anion

The ClC family encompasses two classes of proteins with distinct transport functions: anion channels and transporters. ClC-type transporters usually mediate secondary active anion–proton exchange. However, under certain conditions they assume slippage mode behavior in which proton and anion transport are uncoupled, resulting in passive anion fluxes without associated proton movements. Here, we use patch clamp and intracellular pH recordings on transfected mammalian cells to characterize exchanger and slippage modes of human ClC-4, a member of the ClC transporter branch. We found that the two transport modes differ in transport mechanisms and transport rates. Nonstationary noise analysis revealed a unitary transport rate of 5 × 105 s−1 at +150 mV for the slippage mode, indicating that ClC-4 functions as channel in this mode. In the exchanger mode, unitary transport rates were 10-fold lower. Both ClC-4 transport modes exhibit voltage-dependent gating, indicating that there are active and non-active states for the exchanger as well as for the slippage mode. ClC-4 can assume both transport modes under all tested conditions, with exchanger/channel ratios determined by the external anion. We propose that binding of transported anions to non-active states causes transition from slippage into exchanger mode. Binding and unbinding of anions is very rapid, and slower transitions of liganded and non-liganded states into active conformations result in a stable distribution between the two transport modes. The proposed mechanism results in anion-dependent conversion of ClC-type exchanger into an anion channel with typical attributes of ClC anion channels.

scholarly journals Non-human primate and human malaria: past, present and future

2021 ◽  
Author(s):  
Spinello Antinori ◽  
Cecilia Bonazzetti ◽  
Andrea Giacomelli ◽  
Mario Corbellino ◽  
Massimo Galli ◽  
...  
Keyword(s):  
Plasmodium Knowlesi ◽  
Plasmodium Species ◽  
Molecular Techniques ◽  
Malaria Parasites ◽  
Human Malaria ◽  
Complex Interactions ◽  
Zoonotic Malaria ◽  
The Impact ◽  
Human Plasmodium ◽  
Human Primate

Abstract Background Studies of the malaria parasites infecting various non-human primates (NHPs) have increased our understanding of the origin, biology and pathogenesis of human Plasmodium parasites. This review considers the major discoveries concerning NHP malaria parasites, highlights their relationships with human malaria and considers the impact that this may have on attempts to eradicate the disease. Results The first description of NHP malaria parasites dates back to the early 20th century. Subsequently, experimental and fortuitous findings indicating that some NHP malaria parasites can be transmitted to humans have raised concerns about the possible impact of a zoonotic malaria reservoir on efforts to control human malaria. Advances in molecular techniques over the last 15 years have contributed greatly to our knowledge of the existence and geographical distribution of numerous Plasmodium species infecting NHPs, and extended our understanding of their close phylogenetic relationships with human malaria parasites. The clinical application of such techniques has also made it possible to document ongoing spillovers of NHP malaria parasites (Plasmodium knowlesi, P. cynomolgi, P. simium, P. brasilianum) in humans living in or near the forests of Asia and South America, thus confirming that zoonotic malaria can undermine efforts to eradicate human malaria. Conclusions Increasing molecular research supports the prophetic intuition of the pioneers of modern malariology who saw zoonotic malaria as a potential obstacle to the full success of malaria eradication programmes. It is, therefore, important to continue surveillance and research based on one-health approaches in order to improve our understanding of the complex interactions between NHPs, mosquito vectors and humans during a period of ongoing changes in the climate and the use of land, monitor the evolution of zoonotic malaria, identify the populations most at risk and implement appropriate preventive strategies.

scholarly journals Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death

2007 ◽  
Vol 9 (5) ◽  
pp. 550-555 ◽  
Author(s):  
Christopher P. Baines ◽  
Robert A. Kaiser ◽  
Tatiana Sheiko ◽  
William J. Craigen ◽  
Jeffery D. Molkentin
Keyword(s):  
Cell Death ◽  
Anion Channels ◽  
Voltage Dependent ◽  
Dependent Cell

scholarly journals VDAC1 in the diseased myocardium and the effect of VDAC1-interacting compound on atrial fibrosis induced by hyperaldosteronism

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hadar Klapper-Goldstein ◽  
Ankit Verma ◽  
Sigal Elyagon ◽  
Roni Gillis ◽  
Michael Murninkas ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Apoptotic Cell ◽  
Anion Channel ◽  
Immunohistochemical Analysis ◽  
Voltage Dependent Anion Channel ◽  
Cardiac Tissues ◽  
Therapeutic Implications ◽  
Voltage Dependent ◽  
Models Of Lupus

AbstractThe voltage-dependent anion channel 1 (VDAC1) is a key player in mitochondrial function. VDAC1 serves as a gatekeeper mediating the fluxes of ions, nucleotides, and other metabolites across the outer mitochondrial membrane, as well as the release of apoptogenic proteins initiating apoptotic cell death. VBIT-4, a VDAC1 oligomerization inhibitor, was recently shown to prevent mitochondrial dysfunction and apoptosis, as validated in mouse models of lupus and type-2 diabetes. In the present study, we explored the expression of VDAC1 in the diseased myocardium of humans and rats. In addition, we evaluated the effect of VBIT-4 treatment on the atrial structural and electrical remodeling of rats exposed to excessive aldosterone levels. Immunohistochemical analysis of commercially available human cardiac tissues revealed marked overexpression of VDAC1 in post-myocardial infarction patients, as well as in patients with chronic ventricular dilatation\dysfunction. In agreement, rats exposed to myocardial infarction or to excessive aldosterone had a marked increase of VDAC1 in both ventricular and atrial tissues. Immunofluorescence staining indicated a punctuated appearance typical for mitochondrial-localized VDAC1. Finally, VBIT-4 treatment attenuated the atrial fibrotic load of rats exposed to excessive aldosterone without a notable effect on the susceptibility to atrial fibrillation episodes induced by burst pacing. Our results indicate that VDAC1 overexpression is associated with myocardial abnormalities in common pathological settings. Our data also indicate that inhibition of the VDAC1 can reduce excessive fibrosis in the atrial myocardium, a finding which may have important therapeutic implications. The exact mechanism\s of this beneficial effect need further studies.

More than just a pressure relief valve: physiological roles of volume-regulated LRRC8 anion channels

2019 ◽  
Vol 400 (11) ◽  
pp. 1481-1496 ◽  
Author(s):  
Lingye Chen ◽  
Benjamin König ◽  
Tianbao Liu ◽  
Sumaira Pervaiz ◽  
Yasmin S. Razzaque ◽  
...  
Keyword(s):  
Volume Regulation ◽  
Regulatory Volume Decrease ◽  
Anion Channel ◽  
Therapy Resistance ◽  
Cell Swelling ◽  
Organic Osmolytes ◽  
Anion Channels ◽  
Relief Valve ◽  
Wide Range ◽  
And Migration

Abstract The volume-regulated anion channel (VRAC) is a key player in the volume regulation of vertebrate cells. This ubiquitously expressed channel opens upon osmotic cell swelling and potentially other cues and releases chloride and organic osmolytes, which contributes to regulatory volume decrease (RVD). A plethora of studies have proposed a wide range of physiological roles for VRAC beyond volume regulation including cell proliferation, differentiation and migration, apoptosis, intercellular communication by direct release of signaling molecules and by supporting the exocytosis of insulin. VRAC was additionally implicated in pathological states such as cancer therapy resistance and excitotoxicity under ischemic conditions. Following extensive investigations, 5 years ago leucine-rich repeat-containing family 8 (LRRC8) heteromers containing LRRC8A were identified as the pore-forming components of VRAC. Since then, molecular biological approaches have allowed further insight into the biophysical properties and structure of VRAC. Heterologous expression, siRNA-mediated downregulation and genome editing in cells, as well as the use of animal models have enabled the assessment of the proposed physiological roles, together with the identification of new functions including spermatogenesis and the uptake of antibiotics and platinum-based cancer drugs. This review discusses the recent molecular biological insights into the physiology of VRAC in relation to its previously proposed roles.

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