scholarly journals LRRC8/VRAC Channels and the Redox Balance: A Complex Relationship

2021 ◽  
Vol 55 (S1) ◽  
pp. 106-118
Keyword(s):  
Regulatory Volume Decrease ◽  
Redox System ◽  
Redox Balance ◽  
Research Field ◽  
Complex Relationship ◽  
Anion Channels ◽  
Molecular Identity ◽  
Physiological Processes ◽  
Main Pathway ◽  
Volume Decrease

More than three decades after their first biophysical description, Volume Regulated Anion Channels (VRACs) still remain challenging to understand. Initially, VRACs were identified as the main pathway for the cell to extrude Cl- ions during the regulatory volume decrease (RVD) mechanism contributing in fine to the recovery of normal cell volume. For years, scientists have tried unsuccessfully to find their molecular identity, leading to controversy within the field that only ended in 2014 when two independent groups demonstrated that VRACs were formed by heteromers of LRRC8 proteins. This breakthrough gave a second breath to the research field and was followed by many publications regarding LRRC8/VRACs structure/ function, physiological roles and 3D structures. Nevertheless, far from simplifying the field, these discoveries have instead exponentially increased its complexity. Indeed, the channel's biophysical properties seem to be dependent on the LRRC8 subunits composition with each heteromer showing different ion/molecule permeabilities and regulatory mechanisms. One clear example of this complexity is the intricate relationship between LRRC8/VRACs and the redox system. On one hand, VRACs appear to be directly regulated by oxidation or reduction depending on their subunit composition. On the other hand, VRACs can also impact the redox balance within the cells, through their permeability to reduced glutathione or through other as yet uncharacterized pathways. Unravelling this issue is particularly crucial as LRRC8/VRACs play an important role in a wide variety of physiological processes involving oxidative stress signaling. In this regard, we have tried to systematically identify in the literature both preand post-LRRC8 discovery as well as the interplay between VRACs and the redox system to provide new insights into this complex relationship.

scholarly journals The septin cytoskeleton facilitates membrane retraction during motility and blebbing

2012 ◽  
Vol 196 (1) ◽  
pp. 103-114 ◽  
Author(s):  
Julia K. Gilden ◽  
Sebastian Peck ◽  
Yi-Chun M. Chen ◽  
Matthew F. Krummel
Keyword(s):  
Plasma Membrane ◽  
Dendritic Spines ◽  
Membrane Trafficking ◽  
Shape Change ◽  
Critical Role ◽  
Regulatory Volume Decrease ◽  
Physiological Processes ◽  
Amoeboid Motility ◽  
Dynamic Shape ◽  
Volume Decrease

Increasing evidence supports a critical role for the septin cytoskeleton at the plasma membrane during physiological processes including motility, formation of dendritic spines or cilia, and phagocytosis. We sought to determine how septins regulate the plasma membrane, focusing on this cytoskeletal element’s role during effective amoeboid motility. Surprisingly, septins play a reactive rather than proactive role, as demonstrated during the response to increasing hydrostatic pressure and subsequent regulatory volume decrease. In these settings, septins were required for rapid cortical contraction, and SEPT6-GFP was recruited into filaments and circular patches during global cortical contraction and also specifically during actin filament depletion. Recruitment of septins was also evident during excessive blebbing initiated by blocking membrane trafficking with a dynamin inhibitor, providing further evidence that septins are recruited to facilitate retraction of membranes during dynamic shape change. This function of septins in assembling on an unstable cortex and retracting aberrantly protruding membranes explains the excessive blebbing and protrusion observed in septin-deficient T cells.

The volume-regulated anion channel is formed by LRRC8 heteromers – molecular identification and roles in membrane transport and physiology

2015 ◽  
Vol 396 (9-10) ◽  
pp. 975-990 ◽  
Author(s):  
Tobias Stauber
Keyword(s):  
Cell Biology ◽  
Regulatory Volume Decrease ◽  
Anion Channel ◽  
Cell Swelling ◽  
Transepithelial Transport ◽  
Organic Osmolytes ◽  
Physiological Processes ◽  
Starting Point ◽  
And Migration ◽  
Volume Decrease

Abstract 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. It may also play a role in pathological states like cancer and ischemia. Despite many efforts, the molecular identity of VRAC had remained elusive for decades, until the recent discovery of heteromers of LRRC8A with other LRRC8 family members as an essential VRAC component. This identification marks a starting point for studies on the structure-function relation, for molecular biological investigations of its cell biology and for re-evaluating the physiological roles of VRAC. This review recapitulates the identification of LRRC8 heteromers as VRAC components, depicts the similarities between LRRC8 proteins and pannexins, and discussed whether VRAC conducts larger osmolytes. Furthermore, proposed physiological functions of VRAC and the present knowledge about the physiological significance of LRRC8 proteins are summarized and collated.

GSH depletion, K-Cl cotransport, and regulatory volume decrease in high-K/high-GSH dog red blood cells

2001 ◽  
Vol 281 (6) ◽  
pp. C2003-C2009 ◽  
Author(s):  
Hiroshi Fujise ◽  
Kazunari Higa ◽  
Tomomi Kanemaru ◽  
Miwa Fukuda ◽  
Norma C. Adragna ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Regulatory Volume Decrease ◽  
Cell Volume Regulation ◽  
Redox System ◽  
Glutathione S Transferase ◽  
High Potassium ◽  
High K ◽  
Protein Thiols ◽  
Volume Decrease

Thiol reagents activate K-Cl cotransport (K-Cl COT), the Cl-dependent and Na-independent ouabain-resistant K flux, in red blood cells (RBCs) of several species, upon depletion of cellular glutathione (GSH). K-Cl COT is physiologically active in high potassium (HK), high GSH (HG) dog RBCs. In this unique model, we studied whether the same inverse relationship exists between GSH levels and K-Cl COT activity found in other species. The effects of GSH depletion by three different chemical reactions [nitrite (NO2)-mediated oxidation, diazene dicarboxylic acid bis- N, N-dimethylamide (diamide)-induced dithiol formation, and glutathione S-transferase (GST)-catalyzed conjugation of GSH with 1-chloro-2,4-dinitrobenzene (CDNB)] were tested on K-Cl COT and regulatory volume decrease (RVD). After 85% GSH depletion, all three interventions stimulated K-Cl COT half-maximally with the following order of potency: diamide > NO2 > CDNB. Repletion of GSH reversed K-Cl COT stimulation by 50%. Cl-dependent RVD accompanied K-Cl COT activation by NO2 and diamide. K-Cl COT activation at concentration ratios of oxidant/GSH greater than unity was irreversible, suggesting either nitrosothiolation, heterodithiol formation, or GST-mediated dinitrophenylation of protein thiols. The data support the hypothesis that an intact redox system, rather than the absolute GSH levels, protects K-Cl COT activity and cell volume regulation from thiol modification.

Human Platelets Exposed to Mechanical Stresses Express a Potent Lipoxygenase Product

1992 ◽  
Vol 68 (05) ◽  
pp. 589-594 ◽  
Author(s):  
Alon Margalit ◽  
Avinoam A Livne
Keyword(s):  
Regulatory Volume Decrease ◽  
Human Platelets ◽  
Mechanical Stresses ◽  
Arterial Stenosis ◽  
Platelet Suspension ◽  
Suspension Flows ◽  
Lipoxygenase Product ◽  
Pathological Conditions ◽  
K Permeability ◽  
Volume Decrease

SummaryHuman platelets exposed to hypotonicity undergo regulatory volume decrease (RVD), controlled by a potent, yet labile, lipoxygenase product (LP). LP is synthesized and excreted during RVD affecting selectively K+ permeability. LP is assayed by its capacity to reconstitute RVD when lipoxygenase is blocked. Centrifugation for preparing washed platelets (1,550 × g, 10 min) is sufficient to express LP activity, with declining potency in repeated centrifugations, indicating that it is not readily replenish-able. When platelet suspension flows in a vinyl tubing (1 mm i.d.), at physiological velocity, controlled at 90–254 cm/s, LP formation increases as a function of velocity but declines as result of increasing the tubing length. Stirring the platelets in an aggregometer cuvette for 30 s, yields no LP unless the stirring is intermittent. No associated platelet lysis or aggregation are observed following the mechanical stress applications. These results demonstrate that although mechanical stresses result in LP production, the mode of its application plays a major role. These results may indicate that LP is synthesized under pathological conditions and could be of relevance to platelets behavior related to arterial stenosis.

scholarly journals Overexpression of DUF538 from Wild Arachis Enhances Plant Resistance to Meloidogyne spp.

Agronomy ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 559
Author(s):  
Ana Claudia Guerra Araujo ◽  
Patricia Messenberg Guimaraes ◽  
Ana Paula Zotta Mota ◽  
Larissa Arrais Guimaraes ◽  
Bruna Medeiros Pereira ◽  
...  
Keyword(s):  
Transgenic Plants ◽  
Redox System ◽  
Redox Balance ◽  
Uncharacterized Protein ◽  
Chlorophyll Breakdown ◽  
Domain Of Unknown Function ◽  
Expression Behavior ◽  
Meloidogyne Spp ◽  
Wild Peanut ◽  
First Time

DUF538 proteins belong to a large group of uncharacterized protein families sharing the highly conserved Domain of Unknown Function (DUF). Attention has been given to DUF538 domain-containing proteins due to changes in their gene expression behavior and protein abundance during plant development and responses to stress. Putative roles attributed to DUF538 in plants under abiotic and biotic constraints include involvement in cell redox balance, chlorophyll breakdown and pectin degradation. Our previous transcriptome studies suggested that DUF538 is also involved in the resistance responses of wild Arachis species against the highly hazardous root-knot nematodes (RKNs). To clarify the role of the AsDUF538 gene from the wild peanut relative Arachis stenosperma in this interaction, we analyzed the effect of its overexpression on RKN infection in peanut and soybean hairy roots and Arabidopsis transgenic plants. AsDUF538 overexpression significantly reduced the infection in all three heterologous plant systems against their respective RKN counterparts. The distribution of AsDUF538 transcripts in RKN-infected Arachis roots and the effects of AsDUF538 overexpression on hormonal pathways and redox system in transgenic Arabidopsis were also evaluated. This is the first time that a DUF538 gene is functionally validated in transgenic plants and the earliest report on its role in plant defense against RKNs.

LRRC8A is essential for swelling‐activated chloride current and for regulatory volume decrease in astrocytes

2018 ◽  
Vol 33 (1) ◽  
pp. 101-113 ◽  
Author(s):  
Francesco Formaggio ◽  
Emanuela Saracino ◽  
Maria Grazia Mola ◽  
Shreyas Balachandra Rao ◽  
Mahmood Amiry-Moghaddam ◽  
...  
Keyword(s):  
Regulatory Volume Decrease ◽  
Chloride Current ◽  
Volume Decrease

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.

Comparative analysis of P receptor-mediated induction of regulatory volume decrease in cells from teleosts and mammals

2009 ◽  
Vol 154 (1) ◽  
pp. S29
Author(s):  
C.L. Alvarez ◽  
M.V. Espelt ◽  
D.E. Pafundo ◽  
G. Krumschnabel ◽  
P.J. Schwarzbaum
Keyword(s):  
Comparative Analysis ◽  
Regulatory Volume Decrease ◽  
Volume Decrease ◽  
In Cells

Extracellular pH alkalinization by Cl−/HCO3− exchanger is crucial for TASK2 activation by hypotonic shock in proximal cell lines from mouse kidney

2007 ◽  
Vol 292 (2) ◽  
pp. F628-F638 ◽  
Author(s):  
S. L'Hoste ◽  
H. Barriere ◽  
R. Belfodil ◽  
I. Rubera ◽  
C. Duranton ◽  
...  
Keyword(s):  
Cell Lines ◽  
Regulatory Volume Decrease ◽  
Inhibitory Effect ◽  
Buffering Capacity ◽  
Mouse Kidney ◽  
Wild Type ◽  
Cytosolic Ph ◽  
Hypotonic Shock ◽  
External Ph ◽  
Volume Decrease

We have previously shown that K+-selective TASK2 channels and swelling-activated Cl− currents are involved in a regulatory volume decrease (RVD; Barriere H, Belfodil R, Rubera I, Tauc M, Lesage F, Poujeol C, Guy N, Barhanin J, Poujeol P. J Gen Physiol 122: 177–190, 2003; Belfodil R, Barriere H, Rubera I, Tauc M, Poujeol C, Bidet M, Poujeol P. Am J Physiol Renal Physiol 284: F812–F828, 2003). The aim of this study was to determine the mechanism responsible for the activation of TASK2 channels during RVD in proximal cell lines from mouse kidney. For this purpose, the patch-clamp whole-cell technique was used to test the effect of pH and the buffering capacity of external bath on Cl− and K+ currents during hypotonic shock. In the presence of a high buffer concentration (30 mM HEPES), the cells did not undergo RVD and did not develop outward K+ currents (TASK2). Interestingly, the hypotonic shock reduced the cytosolic pH (pHi) and increased the external pH (pHe) in wild-type but not in cftr −/− cells. The inhibitory effect of DIDS suggests that the acidification of pHi and the alkalinization of pHe induced by hypotonicity in wild-type cells could be due to an exit of HCO3−. In conclusion, these results indicate that Cl− influx will be the driving force for HCO3− exit through the activation of the Cl−/HCO3− exchanger. This efflux of HCO3− then alkalinizes pHe, which in turn activates TASK2 channels.

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