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https://www.readbyqxmd.com/read/27764579/specific-and-essential-but-not-sufficient-roles-of-lrrc8a-in-the-activity-of-volume-sensitive-outwardly-rectifying-anion-channel-vsor
#1
Toshiaki Okada, Md Rafiqul Islam, Nargiza A Tsiferova, Yasunobu Okada, Ravshan Z Sabirov
The broadly expressed volume-sensitive outwardly rectifying anion channel (VSOR, also called VRAC) plays essential roles in cell survival and death. Recent findings have suggested that LRRC8A is a core component of VSOR in human cells. In the present study, VSOR currents were found to be largely reduced by siRNA against LRRC8A in mouse C127 cells as well. In contrast, LRRC8A knockdown never affected activities of four other types of anion channel activated by acid, Ca(2+), patch excision or cAMP. While cisplatin-resistant KCP-4 cells poorly expressed endogenous VSOR activity, molecular expression levels of LRRC8A, LRRC8D and LRRC8E were indistinguishable between VSOR-deficient KCP-4 cells and the parental VSOR-rich KB cells...
October 20, 2016: Channels
https://www.readbyqxmd.com/read/27705766/investigation-of-lrrc8-mediated-volume-regulated-anion-currents-in-xenopus-oocytes
#2
Héctor Gaitán-Peñas, Antonella Gradogna, Lara Laparra-Cuervo, Carles Solsona, Victor Fernández-Dueñas, Alejandro Barrallo-Gimeno, Francisco Ciruela, Melike Lakadamyali, Michael Pusch, Raúl Estévez
Volume-regulated anion channels (VRACs) play an important role in controlling cell volume by opening upon cell swelling. Recent work has shown that heteromers of LRRC8A with other LRRC8 members (B, C, D, and E) form the VRAC. Here, we used Xenopus oocytes as a simple system to study LRRC8 proteins. We discovered that adding fluorescent proteins to the C-terminus resulted in constitutive anion channel activity. Using these constructs, we reproduced previous findings indicating that LRRC8 heteromers mediate anion and osmolyte flux with subunit-dependent kinetics and selectivity...
October 4, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27688432/leucine-rich-repeat-containing-protein-lrrc8a-is-essential-for-swelling-activated-cl-currents-and-embryonic-development-in-zebrafish
#3
Toshiki Yamada, Robert Wondergem, Rebecca Morrison, Viravuth P Yin, Kevin Strange
A volume-regulated anion channel (VRAC) has been electrophysiologically characterized in innumerable mammalian cell types. VRAC is activated by cell swelling and mediates the volume regulatory efflux of Cl(-) and small organic solutes from cells. Two groups recently identified the mammalian leucine-rich repeat containing protein LRRC8A as an essential VRAC component. LRRC8A must be coexpressed with at least one of the other four members of this gene family, LRRC8B-E, to reconstitute VRAC activity in LRRC8(-/-) cells...
October 2016: Physiological Reports
https://www.readbyqxmd.com/read/27579940/distinct-contributions-of-lrrc8a-and-its-paralogs-to-the-vsor-anion-channel-from-those-of-the-asor-anion-channel
#4
Kaori Sato-Numata, Tomohiro Numata, Ryuji Inoue, Ravshan Z Sabirov, Yasunobu Okada
Volume- and acid-sensitive outwardly rectifying anion channels (VSOR and ASOR) activated by swelling and acidification exhibit voltage-dependent inactivation and activation time courses, respectively. Recently, LRRC8A and some paralogs were shown to be essentially involved in the activity and inactivation kinetics of VSOR currents in human colonic HCT116 cells. In human cervix HeLa cells, here, inactivation of VSOR currents was found to become accelerated by RNA silencing only of LRRC8A but never decelerated by that of any LRRC8 isoform...
August 31, 2016: Channels
https://www.readbyqxmd.com/read/27514381/relationship-between-tmem16a-anoctamin-1-and-lrrc8a
#5
Roberta Benedetto, Lalida Sirianant, Ines Pankonien, Podchanart Wanitchakool, Jiraporn Ousingsawat, Ines Cabrita, Rainer Schreiber, Margarida Amaral, Karl Kunzelmann
TMEM16A/anoctamin 1/ANO1 and VRAC/LRRC8 are independent chloride channels activated either by increase in intracellular Ca(2+) or cell swelling, respectively. In previous studies, we observed overlapping properties for both types of channels. (i) TMEM16A/ANO1 and LRRC8 are inhibited by identical compounds, (ii) the volume-regulated anion channel VRAC requires compartmentalized Ca(2+) increase to be fully activated, (iii) anoctamins are activated by cell swelling, (iv) both channels have a role for apoptotic cell death, (v) both channels are possibly located in lipid rafts/caveolae like structures, and (vi) VRAC and anoctamin 1 currents are not additive when each are fully activated...
October 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27325695/inactivation-and-anion-selectivity-of-volume-regulated-anion-channels-vracs-depend-on-c-terminal-residues-of-the-first-extracellular-loop
#6
Florian Ullrich, S Momsen Reincke, Felizia K Voss, Tobias Stauber, Thomas J Jentsch
Canonical volume-regulated anion channels (VRACs) are crucial for cell volume regulation and have many other important roles, including tumor drug resistance and release of neurotransmitters. Although VRAC-mediated swelling-activated chloride currents (ICl,vol) have been studied for decades, exploration of the structure-function relationship of VRAC has become possible only after the recent discovery that VRACs are formed by differently composed heteromers of LRRC8 proteins. Inactivation of ICl,vol at positive potentials, a typical hallmark of VRACs, strongly varies between native cell types...
August 12, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27270446/cl-channels-in-apoptosis
#7
Podchanart Wanitchakool, Jiraporn Ousingsawat, Lalida Sirianant, Nanna MacAulay, Rainer Schreiber, Karl Kunzelmann
A remarkable feature of apoptosis is the initial massive cell shrinkage, which requires opening of ion channels to allow release of K(+), Cl(-), and organic osmolytes to drive osmotic water movement and cell shrinkage. This article focuses on the role of the Cl(-) channels LRRC8, TMEM16/anoctamin, and cystic fibrosis transmembrane conductance regulator (CFTR) in cellular apoptosis. LRRC8A-E has been identified as a volume-regulated anion channel expressed in many cell types. It was shown to be required for regulatory and apoptotic volume decrease (RVD, AVD) in cultured cell lines...
June 7, 2016: European Biophysics Journal: EBJ
https://www.readbyqxmd.com/read/27033257/vracs-and-other-ion-channels-and-transporters-in-the-regulation-of-cell-volume-and-beyond
#8
Thomas J Jentsch
Cells need to regulate their volume to counteract osmotic swelling or shrinkage, as well as during cell division, growth, migration and cell death. Mammalian cells adjust their volume by transporting potassium, sodium, chloride and small organic osmolytes using plasma membrane channels and transporters. This generates osmotic gradients, which drive water in and out of cells. Key players in this process are volume-regulated anion channels (VRACs), the composition of which has recently been identified and shown to encompass LRRC8 heteromers...
May 2016: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/26873248/non-essential-contribution-of-lrrc8a-to-volume-regulation
#9
Lalida Sirianant, Podchanart Wanitchakool, Jiraporn Ousingsawat, Roberta Benedetto, Anna Zormpa, Ines Cabrita, Rainer Schreiber, Karl Kunzelmann
Volume regulation is an essential property of any living cell and needs to be tightly controlled. While different types of K(+) channels have been found to participate in the regulation of cell volume, the newly identified volume-regulated anion channel (VRAC) LRRC8 has been claimed to be essential for volume regulation. In unbiased genome-wide small interfering RNA (siRNA) screens, two independent studies identified LRRC8A/Swell1 as an essential component of VRAC, thus being indispensable for cellular volume regulation...
May 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/26824658/lrrc8-proteins-form-volume-regulated-anion-channels-that-sense-ionic-strength
#10
Ruhma Syeda, Zhaozhu Qiu, Adrienne E Dubin, Swetha E Murthy, Maria N Florendo, Daniel E Mason, Jayanti Mathur, Stuart M Cahalan, Eric C Peters, Mauricio Montal, Ardem Patapoutian
The volume-regulated anion channel (VRAC) is activated when a cell swells, and it plays a central role in maintaining cell volume in response to osmotic challenges. SWELL1 (LRRC8A) was recently identified as an essential component of VRAC. However, the identity of the pore-forming subunits of VRAC and how the channel is gated by cell swelling are unknown. Here, we show that SWELL1 and up to four other LRRC8 subunits assemble into heterogeneous complexes of ∼800 kDa. When reconstituted into bilayers, LRRC8 complexes are sufficient to form anion channels activated by osmolality gradients...
January 28, 2016: Cell
https://www.readbyqxmd.com/read/26743872/distinct-pharmacological-and-molecular-properties-of-the-acid-sensitive-outwardly-rectifying-asor-anion-channel-from-those-of-the-volume-sensitive-outwardly-rectifying-vsor-anion-channel
#11
Kaori Sato-Numata, Tomohiro Numata, Ryuji Inoue, Yasunobu Okada
Expressed by many cell types, acid-sensitive outwardly rectifying (ASOR) anion channels are known to be activated by extracellular acidification and involved in acidotoxic necrotic cell death. In contrast, ubiquitously expressed volume-sensitive outwardly rectifying (VSOR) anion channels are activated by osmotic cell swelling and involved in cell volume regulation and apoptotic cell death. Distinct inhibitors to distinguish ASOR from VSOR anion channels have not been identified. Although leucine-rich repeats containing 8A (LRRC8A) was recently found to be an essential component of VSOR anion channels, the possibility of an LRRC8 family member serving as a component of ASOR anion channels has not been examined...
May 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/26739710/biophysics-and-physiology-of-the-volume-regulated-anion-channel-vrac-volume-sensitive-outwardly-rectifying-anion-channel-vsor
#12
REVIEW
Stine F Pedersen, Yasunobu Okada, Bernd Nilius
The volume-regulated anion channel (VRAC), also known as the volume-sensitive outwardly rectifying (VSOR) anion channel or the volume-sensitive organic osmolyte/anion channel (VSOAC), is essential for cell volume regulation after swelling in most vertebrate cell types studied to date. In addition to its role in cell volume homeostasis, VRAC has been implicated in numerous other physiological and pathophysiological processes, including cancer, ischemic brain edema, cell motility, proliferation, angiogenesis, programmed cell death, and excitotoxic glutamate release...
March 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/26635246/vrac-molecular-identification-as-lrrc8-heteromers-with-differential-functions
#13
Thomas J Jentsch, Darius Lutter, Rosa Planells-Cases, Florian Ullrich, Felizia K Voss
A major player of vertebrate cell volume regulation is the volume-regulated anion channel (VRAC), which conducts halide ions and organic osmolytes to counteract osmotic imbalances. The molecular entity of this channel was unknown until very recently, although its biophysical characteristics and diverse physiological roles have been extensively studied over the last 30 years. On the road to the molecular identification of VRAC, experimental difficulties led to the proposal of a variety of false candidates. In 2014, in a final breakthrough, two groups independently identified LRRC8A as indispensable component of VRAC...
March 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/26620797/volume-regulated-anion-channel-a-frenemy-within-the-brain
#14
REVIEW
Alexander A Mongin
The volume-regulated anion channel (VRAC) is a ubiquitously expressed yet highly enigmatic member of the superfamily of chloride/anion channels. It is activated by cellular swelling and mediates regulatory cell volume decrease in a majority of vertebrate cells, including those in the central nervous system (CNS). In the brain, besides its crucial role in cellular volume regulation, VRAC is thought to play a part in cell proliferation, apoptosis, migration, and release of physiologically active molecules. Although these roles are not exclusive to the CNS, the relative significance of VRAC in the brain is amplified by several unique aspects of its physiology...
March 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/26603282/calcium-homeostasis-modulator-calhm-ion-channels
#15
REVIEW
Zhongming Ma, Jessica E Tanis, Akiyuki Taruno, J Kevin Foskett
Calcium homeostasis modulator 1 (CALHM1), formerly known as FAM26C, was recently identified as a physiologically important plasma membrane ion channel. CALHM1 and its Caenorhabditis elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca(2+) concentration ([Ca(2+)]o). In the presence of physiological [Ca(2+)]o (∼1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations. Reducing [Ca(2+)]o increases channel open probability, enabling channel activation at negative membrane potentials...
March 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/26530471/subunit-composition-of-vrac-channels-determines-substrate-specificity-and-cellular-resistance-to-pt-based-anti-cancer-drugs
#16
Rosa Planells-Cases, Darius Lutter, Charlotte Guyader, Nora M Gerhards, Florian Ullrich, Deborah A Elger, Asli Kucukosmanoglu, Guotai Xu, Felizia K Voss, S Momsen Reincke, Tobias Stauber, Vincent A Blomen, Daniel J Vis, Lodewyk F Wessels, Thijn R Brummelkamp, Piet Borst, Sven Rottenberg, Thomas J Jentsch
Although platinum-based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume-regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8-dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC...
December 14, 2015: EMBO Journal
https://www.readbyqxmd.com/read/26438191/cellular-volume-regulation-by-anoctamin-6-ca%C3%A2-%C3%A2-%C2%BA-phospholipase-a2-and-osmosensing
#17
Lalida Sirianant, Jiraporn Ousingsawat, Podchanart Wanitchakool, Rainer Schreiber, Karl Kunzelmann
During cell swelling, Cl(-) channels are activated to lower intracellular Cl(-) concentrations and to reduce cell volume, a process termed regulatory volume decrease (RVD). We show that anoctamin 6 (ANO6; TMEM16F) produces volume-regulated anion currents and controls cell volume in four unrelated cell types. Volume regulation is compromised in freshly isolated intestinal epithelial cells from Ano6-/- mice and also in lymphocytes from a patient lacking expression of ANO6. Ca(2+) influx is activated and thus ANO6 is stimulated during cell swelling by local Ca(2+) increase probably in functional nanodomains near the plasma membrane...
February 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/26254230/tmem16-lrrc8a-bestrophin-chloride-channels-controlled-by-ca-2-and-cell-volume
#18
REVIEW
Karl Kunzelmann
For many years Cl(-) transport by ion channels that are controlled by intracellular Ca(2+) or by cell volume remained enigmatic because their molecular identity was unknown. Recent years, however, have shown remarkable progress, and these channels have been identified as TMEM16A (anoctamin 1), LRRC8A (swell 1), and bestrophin 1 (BEST1), and structural information is already available for the Ca(2+)-activated channels bestrophin and TMEM16. While the structure of bestrophin revealed it is an anion-permeable pore, only indirect evidence exists that TMEM16 and LRRC8 form anion channels...
September 2015: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/25868000/the-volume-regulated-anion-channel-is-formed-by-lrrc8-heteromers-%C3%A2-molecular-identification-and-roles-in-membrane-transport-and-physiology
#19
REVIEW
Tobias Stauber
Cellular volume regulation is fundamental for numerous physiological processes. The volume-regulated anion channel, VRAC, plays a crucial role in regulatory volume decrease. This channel, which is ubiquitously expressed in vertebrates, has been vastly characterized by electrophysiological means. It opens upon cell swelling and conducts chloride and arguably organic osmolytes. VRAC has been proposed to be critically involved in various cellular and organismal functions, including cell proliferation and migration, apoptosis, transepithelial transport, swelling-induced exocytosis and intercellular communication...
September 2015: Biological Chemistry
https://www.readbyqxmd.com/read/25588975/regulation-of-vascular-tone-and-arterial-blood-pressure-role-of-chloride-transport-in-vascular-smooth-muscle
#20
REVIEW
Christian A Hübner, Björn C Schroeder, Heimo Ehmke
Recent studies suggest that primary changes in vascular resistance can cause sustained changes in arterial blood pressure. In this review, we summarize current knowledge about Cl(-) homeostasis in vascular smooth muscle cells. Within vascular smooth muscle cells, Cl(-) is accumulated above the electrochemical equilibrium, causing Cl(-) efflux, membrane depolarization, and increased contractile force when Cl(-) channels are opened. At least two different transport mechanisms contribute to raise [Cl(-)] i in vascular smooth muscle cells, anion exchange, and cation-chloride cotransport...
March 2015: Pflügers Archiv: European Journal of Physiology
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