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Akiyuki Taruno
Adenosine triphosphate (ATP) has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological and pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms of cellular ATP release have been demonstrated in many cell types. Although large and negatively charged ATP molecules cannot diffuse across the lipid bilayer of the plasma membrane, conductive ATP release from the cytosol into the extracellular space is possible through ATP-permeable channels...
March 11, 2018: International Journal of Molecular Sciences
Héctor Gaitán-Peñas, Michael Pusch, Raúl Estévez
Volume-regulated anion channels (VRACs) play a role in controlling cell volume by opening upon cell swelling. Apart from controlling cell volume, their function is important in many other physiological processes, such as transport of metabolites or drugs, and extracellular signal transduction. VRACs are formed by heteromers of the pannexin homologous protein LRRC8A (also named Swell1) with other LRRC8 members (B, C, D, and E). LRRC8 proteins are difficult to study, since they are expressed in all cells of our body, and the channel stoichiometry can be changed by overexpression, resulting in non-functional heteromers...
March 2, 2018: International Journal of Molecular Sciences
Corinne S Wilson, Alexander A Mongin
It is well known that the electrical signaling in neuronal networks is modulated by chloride (Cl-) fluxes via the inhibitory GABAA and glycine receptors. Here, we discuss the putative contribution of Cl- fluxes and intracellular Cl- to other forms of information transfer in the CNS, namely the bidirectional communication between neurons and astrocytes. The manuscript (i) summarizes the generic functions of Cl- in cellular physiology, (ii) recaps molecular identities and properties of Cl- transporters and channels in neurons and astrocytes, and (iii) analyzes emerging studies implicating Cl- in the modulation of neuroglial communication...
January 9, 2018: Neuroscience Letters
Raúl Estévez, Xabier Elorza-Vidal, Héctor Gaitán-Peñas, Carla Pérez-Rius, Mercedes Armand-Ugón, Marta Alonso-Gardón, Efren Xicoy-Espaulella, Sònia Sirisi, Tanit Arnedo, Xavier Capdevila-Nortes, Tania López-Hernández, Marisol Montolio, Anna Duarri, Oscar Teijido, Alejandro Barrallo-Gimeno, Manuel Palacín, Virginia Nunes
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy characterized by dysfunction of the role of glial cells in controlling brain fluid and ion homeostasis. Patients affected by MLC present macrocephaly, cysts and white matter vacuolation, which lead to motor and cognitive impairments. To date, there is no treatment for MLC, only supportive care. MLC is caused by mutations in the MLC1 and GLIALCAM genes. MLC1 is a membrane protein with low identity to the Kv1.1 potassium channel and GlialCAM belongs to an adhesion molecule family...
October 25, 2017: European Journal of Medical Genetics
Jonas Friard, Isabelle Rubera, Christophe Duranton
No abstract text is available yet for this article.
November 1, 2017: Journal of Physiology
Litao Xie, Yanhui Zhang, Susheel K Gunasekar, Anil Mishra, Lei Cao, Rajan Sah
Obesity is associated with a loss of insulin-sensitivity and systemic dysglycemia, resulting in Type 2 diabetes, however the molecular mechanisms underlying this association are unclear. Through adipocyte patch-clamp studies, we recently showed that SWELL1 is required for the Volume-Regulated Anion Current (VRAC) in adipocytes and that SWELL1-mediated VRAC is activated by both mechanical and pathophysiological adipocyte expansion. We also demonstrated that adipocyte SWELL1 is required for maintaining insulin signaling and glucose homeostasis, particularly in the setting of obesity...
September 5, 2017: Channels
Antonella Gradogna, Paola Gavazzo, Anna Boccaccio, Michael Pusch
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...
November 1, 2017: Journal of Physiology
Alexandra L Schober, Corinne S Wilson, Alexander A Mongin
KEY POINTS: The volume-regulated anion channel (VRAC) is a swelling-activated chloride channel that is permeable to inorganic anions and a variety of small organic molecules. VRAC is formed via heteromerization of LRRC8 proteins, among which LRRC8A is essential, while LRRC8B/C/D/E serve as exchangeable complementary partners. We used an RNAi approach and radiotracer assays to explore which LRRC8 isoforms contribute to swelling-activated release of diverse organic osmolytes in rat astrocytes...
November 15, 2017: Journal of Physiology
Xu Fei, Yacine Elhmidi, Bengui Zhang, Hong Tang, Da Zhu, Yucheng Chen, Yingqiang Guo
BACKGROUND: To evaluate the safety and efficacy of transcatheter aortic valve implantation (TAVI) for high-risk patients with aortic stenosis using the J-Valve system. METHODS: 30 high-risk patients with severe AS underwent TAVI procedure were enrolled with mean age 74.5±4.5 years and mean logistic Euro-SCORE-I of 28.4±9.6%. All patients were followed up for six months. Outcomes were analyzed in accordance with the updated standardised endpoints defined by the Valve Academic Research Consortium -2 (VRAC-2) criteria...
August 8, 2017: Heart, Lung & Circulation
Jonas Friard, Michel Tauc, Marc Cougnon, Vincent Compan, Christophe Duranton, Isabelle Rubera
Chloride channels play an essential role in a variety of physiological functions and in human diseases. Historically, the field of chloride channels has long been neglected owing to the lack of powerful selective pharmacological agents that are needed to overcome the technical challenge of characterizing the molecular identities of these channels. Recently, members of the LRRC8 family have been shown to be essential for generating the volume-regulated anion channel (VRAC) current, a chloride conductance that governs the regulatory volume decrease (RVD) process...
2017: Frontiers in Pharmacology
Dimitri Defrance, Gilles Ramstein, Sylvie Charbit, Mathieu Vrac, Adjoua Moïse Famien, Benjamin Sultan, Didier Swingedouw, Christophe Dumas, François Gemenne, Jorge Alvarez-Solas, Jean-Paul Vanderlinden
The acceleration of ice sheet melting has been observed over the last few decades. Recent observations and modeling studies have suggested that the ice sheet contribution to future sea level rise could have been underestimated in the latest Intergovernmental Panel on Climate Change report. The ensuing freshwater discharge coming from ice sheets could have significant impacts on global climate, and especially on the vulnerable tropical areas. During the last glacial/deglacial period, megadrought episodes were observed in the Sahel region at the time of massive iceberg surges, leading to large freshwater discharges...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
Yanhui Zhang, Litao Xie, Susheel K Gunasekar, Dan Tong, Anil Mishra, William J Gibson, Chuansong Wang, Trevor Fidler, Brodie Marthaler, Aloysius Klingelhutz, E Dale Abel, Isaac Samuel, Jessica K Smith, Lei Cao, Rajan Sah
Adipocytes undergo considerable volumetric expansion in the setting of obesity. It has been proposed that such marked increases in adipocyte size may be sensed via adipocyte-autonomous mechanisms to mediate size-dependent intracellular signalling. Here, we show that SWELL1 (LRRC8a), a member of the Leucine-Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VRAC) in adipocytes. We find that SWELL1-mediated VRAC is augmented in hypertrophic murine and human adipocytes in the setting of obesity...
May 2017: Nature Cell Biology
(no author information available yet)
No abstract text is available yet for this article.
March 15, 2017: Journal of Cell Science
Runping Wang, Yongjun Lu, Susheel Gunasekar, Yanhui Zhang, Christopher J Benson, Mark W Chapleau, Rajan Sah, François M Abboud
The leucine rich repeat containing protein 8A (LRRC8A), or SWELL1, is an essential component of the volume-regulated anion channel (VRAC) that is activated by cell swelling and ionic strength. We report here for the first time to our knowledge its expression in a primary cell culture of nodose ganglia neurons and its localization in the soma, neurites, and neuronal membrane. We show that this neuronal VRAC/SWELL1 senses low external pH (pHo) in addition to hypoosmolarity. A robust sustained chloride current is seen in 77% of isolated nodose neurons following brief exposures to extracellular acid pH...
March 9, 2017: JCI Insight
Darius Lutter, Florian Ullrich, Jennifer C Lueck, Stefan Kempa, Thomas J Jentsch
In response to swelling, mammalian cells release chloride and organic osmolytes through volume-regulated anion channels (VRACs). VRACs are heteromers of LRRC8A and other LRRC8 isoforms (LRRC8B to LRRC8E), which are co-expressed in HEK293 and most other cells. The spectrum of VRAC substrates and its dependence on particular LRRC8 isoforms remains largely unknown. We show that, besides the osmolytes taurine and myo-inositol, LRRC8 channels transport the neurotransmitters glutamate, aspartate and γ-aminobutyric acid (GABA) and the co-activator D-serine...
March 15, 2017: Journal of Cell Science
Craig D Platt, Janet Chou, Patrick Houlihan, Yousef R Badran, Lalit Kumar, Wayne Bainter, P Luigi Poliani, Carlos J Perez, Sharon Y R Dent, David E Clapham, Fernando Benavides, Raif S Geha
BACKGROUND: Leucine-rich repeat containing 8A (LRRC8A) is an ubiquitously expressed transmembrane protein with 17 leucine-rich repeats (LRRs) at its C-terminal end and is an essential component of the volume-regulated anion channel (VRAC), which controls cellular volume. A heterozygous mutation in LRRC8A that truncates the 2 terminal LRRs was reported in a patient with agammaglobulinemia and absent B cells and was demonstrated to exert a dominant negative effect on T- and B-cell development in mice...
December 2017: Journal of Allergy and Clinical Immunology
Akiyuki Taruno, Yoshinori Marunaka
To maintain cellular and bodily homeostasis, cells respond to extracellular stimuli including osmotic stress by activating various ion channels, which have been implicated in many physiological and pathophysiological conditions. However, cellular osmosensory mechanisms remain elusive. Here, we report a novel voltage-dependent current in N2a cells activated by exposure to hypotonic stress. After a hypotonic challenge, N2a cells sequentially develop two distinct currents. The volume-regulated anion channel (VRAC) current emerges first and, after a delay, activation of a previously uncharacterized strongly outwardly rectifying current follows...
March 4, 2017: Biochemical and Biophysical Research Communications
Antonella Gradogna, Héctor Gaitán-Peñas, Anna Boccaccio, Raúl Estévez, Michael Pusch
LRRC8 proteins have been shown to underlie the ubiquitous volume regulated anion channel (VRAC). VRAC channels are composed of the LRRC8A subunit and at least one among the LRRC8B-E subunits. In addition to their role in volume regulation, LRRC8 proteins have been implicated in the uptake of chemotherapeutic agents. We had found that LRRC8 channels can be conveniently expressed in Xenopus oocytes, a system without endogenous VRAC activity. The fusion with fluorescent proteins yielded constitutive activity for A/C, A/D and A/E heteromers...
May 4, 2017: Channels
Subhash C Basak, Marjan Vrac Ko, Frank A Witzmann
No abstract text is available yet for this article.
2016: Current Computer-aided Drug Design
Olga Ponomarchuk, Francis Boudreault, Sergei N Orlov, Ryszard Grygorczyk
Maintenance of cell volume is a fundamental housekeeping function in eukaryotic cells. Acute cell swelling activates a regulatory volume decrease (RVD) process with poorly defined volume sensing and intermediate signaling mechanisms. Here, we analyzed the putative role of Ca(2+) signaling in RVD in single substrate-adherent human lung epithelial A549 cells. Acute cell swelling was induced by perfusion of the flow-through imaging chamber with 50 % hypotonic solution at a defined fluid turnover rate. Changes in cytosolic Ca(2+) concentration ([Ca(2+)]i) and cell volume were monitored simultaneously with ratiometric Fura-2 fluorescence and 3D reconstruction of stereoscopic single-cell images, respectively...
November 2016: Pflügers Archiv: European Journal of Physiology
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