scholarly journals A 30-year journey from volume-regulated anion currents to molecular structure of the LRRC8 channel

2019 ◽  
Vol 151 (2) ◽  
pp. 100-117 ◽  
Author(s):  
Kevin Strange ◽  
Toshiki Yamada ◽  
Jerod S. Denton
Keyword(s):  
Structure Function ◽  
Cell Volume ◽  
Cell Volume Regulation ◽  
Anion Channel ◽  
Clear Understanding ◽  
Physiological Processes ◽  
Heteromeric Channel ◽  
Key Aspects ◽  
And Function ◽  
Vexing Problem

The swelling-activated anion channel VRAC has fascinated and frustrated physiologists since it was first described in 1988. Multiple laboratories have defined VRAC’s biophysical properties and have shown that it plays a central role in cell volume regulation and possibly other fundamental physiological processes. However, confusion and intense controversy surrounding the channel’s molecular identity greatly hindered progress in the field for >15 yr. A major breakthrough came in 2014 with the demonstration that VRAC is a heteromeric channel encoded by five members of the Lrrc8 gene family, Lrrc8A–E. A mere 4 yr later, four laboratories described cryo-EM structures of LRRC8A homomeric channels. As the melee of structure/function and physiology studies begins, it is critical that this work be framed by a clear understanding of VRAC biophysics, regulation, and cellular physiology as well as by the field’s past confusion and controversies. That understanding is essential for the design and interpretation of structure/function studies, studies of VRAC physiology, and studies aimed at addressing the vexing problem of how the channel detects cell volume changes. In this review we discuss key aspects of VRAC biophysics, regulation, and function and integrate these into our emerging understanding of LRRC8 protein structure/function.

scholarly journals Release of taurine and glutamate contributes to cell volume regulation in human retinal Müller cells: differences in modulation by calcium

2018 ◽  
Vol 120 (3) ◽  
pp. 973-984 ◽  
Author(s):  
Vanina Netti ◽  
Alejandro Pizzoni ◽  
Martha Pérez-Domínguez ◽  
Paula Ford ◽  
Herminia Pasantes-Morales ◽  
...  
Keyword(s):  
Cell Volume ◽  
Regulatory Volume Decrease ◽  
Cell Volume Regulation ◽  
Müller Cells ◽  
Anion Channel ◽  
Müller Cell ◽  
Regulatory Mechanisms ◽  
Muller Cells ◽  
Muller Cell ◽  
Volume Decrease

Neuronal activity in the retina generates osmotic gradients that lead to Müller cell swelling, followed by a regulatory volume decrease (RVD) response, partially due to the isoosmotic efflux of KCl and water. However, our previous studies in a human Müller cell line (MIO-M1) demonstrated that an important fraction of RVD may also involve the efflux of organic solutes. We also showed that RVD depends on the swelling-induced Ca2+ release from intracellular stores. Here we investigate the contribution of taurine (Tau) and glutamate (Glu), the most relevant amino acids in Müller cells, to RVD through the volume-regulated anion channel (VRAC), as well as their Ca2+ dependency in MIO-M1 cells. Swelling-induced [3H]Tau/[3H]Glu release was assessed by radiotracer assays and cell volume by fluorescence videomicroscopy. Results showed that cells exhibited an osmosensitive efflux of [3H]Tau and [3H]Glu (Tau > Glu) blunted by VRAC inhibitors 4-(2-butyl-6,7-dichloro-2-cyclopentylindan-1-on-5-yl)-oxybutyric acid and carbenoxolone reducing RVD. Only [3H]Tau efflux was mainly dependent on Ca2+ release from intracellular stores. RVD was unaffected in a Ca2+-free medium, probably due to Ca2+-independent Tau and Glu release, but was reduced by chelating intracellular Ca2+. The inhibition of phosphatidylinositol-3-kinase reduced [3H]Glu efflux but also the Ca2+-insensitive [3H]Tau fraction and decreased RVD, providing evidence of the relevance of this Ca2+-independent pathway. We propose that VRAC-mediated Tau and Glu release has a relevant role in RVD in Müller cells. The observed disparities in Ca2+ influence on amino acid release suggest the presence of VRAC isoforms that may differ in substrate selectivity and regulatory mechanisms, with important implications for retinal physiology. NEW & NOTEWORTHY The mechanisms for cell volume regulation in retinal Müller cells are still unknown. We show that swelling-induced taurine and glutamate release mediated by the volume-regulated anion channel (VRAC) largely contributes the to the regulatory volume decrease response in a human Müller cell line. Interestingly, the hypotonic-induced efflux of these amino acids exhibits disparities in Ca2+-dependent and -independent regulatory mechanisms, which strongly suggests that Müller cells may express different VRAC heteromers formed by the recently discovered leucine-rich repeat containing 8 (LRRC8) proteins.

scholarly journals Cell Death Induction and Protection by Activation of Ubiquitously Expressed Anion/Cation Channels. Part 2: Functional and Molecular Properties of ASOR/PAC Channels and Their Roles in Cell Volume Dysregulation and Acidotoxic Cell Death

2021 ◽  
Vol 9 ◽  
Author(s):  
Yasunobu Okada ◽  
Kaori Sato-Numata ◽  
Ravshan Z. Sabirov ◽  
Tomohiro Numata
Keyword(s):  
Cell Death ◽  
Cell Volume ◽  
Apoptotic Cell ◽  
Cell Volume Regulation ◽  
Anion Channel ◽  
Cell Swelling ◽  
Dimensional Structure ◽  
Cation Channels ◽  
Anion Channels ◽  
Animal Cells

For survival and functions of animal cells, cell volume regulation (CVR) is essential. Major hallmarks of necrotic and apoptotic cell death are persistent cell swelling and shrinkage, and thus they are termed the necrotic volume increase (NVI) and the apoptotic volume decrease (AVD), respectively. A number of ubiquitously expressed anion and cation channels play essential roles not only in CVR but also in cell death induction. This series of review articles address the question how cell death is induced or protected with using ubiquitously expressed ion channels such as swelling-activated anion channels, acid-activated anion channels, and several types of TRP cation channels including TRPM2 and TRPM7. In the Part 1, we described the roles of swelling-activated VSOR/VRAC anion channels. Here, the Part 2 focuses on the roles of the acid-sensitive outwardly rectifying (ASOR) anion channel, also called the proton-activated chloride (PAC) anion channel, which is activated by extracellular protons in a manner sharply dependent on ambient temperature. First, we summarize phenotypical properties, the molecular identity, and the three-dimensional structure of ASOR/PAC. Second, we highlight the unique roles of ASOR/PAC in CVR dysfunction and in the induction of or protection from acidotoxic cell death under acidosis and ischemic conditions.

scholarly journals Swelling-activated Gd3+-sensitive Cation Current and Cell Volume Regulation in Rabbit Ventricular Myocytes

1997 ◽  
Vol 110 (3) ◽  
pp. 297-312 ◽  
Author(s):  
Henry F. Clemo ◽  
Clive M. Baumgarten
Keyword(s):  
Cell Volume ◽  
Volume Change ◽  
Volume Regulation ◽  
Ventricular Myocytes ◽  
Cell Volume Regulation ◽  
Hill Coefficient ◽  
Physiological Processes ◽  
Cation Current ◽  
Voltage Dependent ◽  
Rabbit Ventricular Myocytes

The role of swelling-activated currents in cell volume regulation is unclear. Currents elicited by swelling rabbit ventricular myocytes in solutions with 0.6–0.9× normal osmolarity were studied using amphotericin perforated patch clamp techniques, and cell volume was examined concurrently by digital video microscopy. Graded swelling caused graded activation of an inwardly rectifying, time-independent cation current (ICir,swell) that was reversibly blocked by Gd3+, but ICir,swell was not detected in isotonic or hypertonic media. This current was not related to IK1 because it was insensitive to Ba2+. The PK/PNa ratio for ICir,swell was 5.9 ± 0.3, implying that inward current is largely Na+ under physiological conditions. Increasing bath K+ increased gCir,swell but decreased rectification. Gd3+ block was fitted with a K0.5 of 1.7 ± 0.3 μM and Hill coefficient, n, of 1.7 ± 0.4. Exposure to Gd3+ also reduced hypotonic swelling by up to ∼30%, and block of current preceded the volume change by ∼1 min. Gd3+-induced cell shrinkage was proportional to ICir,swell when ICir,swell was varied by graded swelling or Gd3+ concentration and was voltage dependent, reflecting the voltage dependence of ICir,swell. Integrating the blocked ion flux and calculating the resulting change in osmolarity suggested that ICir,swell was sufficient to explain the majority of the volume change at –80 mV. In addition, swelling activated an outwardly rectifying Cl− current, ICl,swell. This current was absent after Cl− replacement, reversed at ECl, and was blocked by 1 mM 9-anthracene carboxylic acid. Block of ICl,swell provoked a 28% increase in swelling in hypotonic media. Thus, both cation and anion swelling-activated currents modulated the volume of ventricular myocytes. Besides its effects on cell volume, ICir,swell is expected to cause diastolic depolarization. Activation of ICir,swell also is likely to affect contraction and other physiological processes in myocytes.

scholarly journals Properties, Structures, and Physiological Roles of Three Types of Anion Channels Molecularly Identified in the 2010’s

2021 ◽  
Vol 12 ◽  
Author(s):  
Yasunobu Okada ◽  
Ravshan Z. Sabirov ◽  
Petr G. Merzlyak ◽  
Tomohiro Numata ◽  
Kaori Sato-Numata
Keyword(s):  
Cell Volume ◽  
Structural Properties ◽  
Molecular Identification ◽  
Volume Regulation ◽  
Cell Volume Regulation ◽  
Anion Channel ◽  
Review Article ◽  
Regulatory Proteins ◽  
Anion Channels ◽  
The Core

Molecular identification was, at last, successfully accomplished for three types of anion channels that are all implicated in cell volume regulation/dysregulation. LRRC8A plus LRRC8C/D/E, SLCO2A1, and TMEM206 were shown to be the core or pore-forming molecules of the volume-sensitive outwardly rectifying anion channel (VSOR) also called the volume-regulated anion channel (VRAC), the large-conductance maxi-anion channel (Maxi-Cl), and the acid-sensitive outwardly rectifying anion channel (ASOR) also called the proton-activated anion channel (PAC) in 2014, 2017, and 2019, respectively. More recently in 2020 and 2021, we have identified the S100A10-annexin A2 complex and TRPM7 as the regulatory proteins for Maxi-Cl and VSOR/VRAC, respectively. In this review article, we summarize their biophysical and structural properties as well as their physiological roles by comparing with each other on the basis of their molecular insights. We also point out unsolved important issues to be elucidated soon in the future.

scholarly journals Tannins, novel inhibitors of the volume regulation and the volume-sensitive anion channel

2019 ◽  
Vol 66 (2) ◽  
pp. 37-44 ◽  
Author(s):  
N.A. Tsiferova ◽  
O. J. Khamidova ◽  
A. U. Amonov ◽  
M. B. Rakhimova ◽  
S. I. Rustamova ◽  
...  
Keyword(s):  
Cell Volume ◽  
Volume Regulation ◽  
Cell Volume Regulation ◽  
Anion Channel ◽  
Regulation System ◽  
Hydrolysable Tannins ◽  
Rhus Typhina ◽  
Higher Doses ◽  
Specific Membrane ◽  
Hct116 Cells

Abstract The volume-sensitive outwardly rectifying anion channel (VSOR) is a key component of volume regulation system critical for cell survival in non-isosmotic conditions. The aim of the present study was to test the effects of four tannin extracts with defined compositions on cell volume regulation and VSOR. Preparation I (98% of hydrolysable tannins isolated from leaves of sumac Rhus typhina L.) and Preparation II (100% of hydrolysable tannins isolated from leaves of broadleaf plantain Plantago major L) completely and irreversibly abolished swelling-activated VSOR currents in HCT116 cells. Both preparations profoundly suppressed the volume regulation in thymocytes with half-maximal effects of 40.9 μg/ml and 12.3 μg/ml, respectively. The inhibition was more efficient at lower concentrations but reverted at higher doses due to possible non-specific membrane-permeabilizing activity. Preparations III and IV (54,7% and 54.3% of hydrolysable tannins isolated, respectively, from roots and aboveground parts of Fergana spurge Euphorbia ferganensis B.Fedtch) inhibited VSOR activity in a partially reversible manner and suppressed the volume regulation with substantially higher half-maximal doses of 270 and 278 μg/ml, respectively, with no secondary reversion at higher doses. Hydrolysable tannins represent a novel class of VSOR channel inhibitors with the capacity to suppress the cell volume regulation machinery.

Microfluidic Cell Volume Biosensor for High Throughput Drug Screening

2004 ◽  
Vol 845 ◽  
Author(s):  
Daniel A. Ateya ◽  
Frederick Sachs ◽  
Susan Z. Hua
Keyword(s):  
Cell Volume ◽  
Volume Change ◽  
Cell Volume Regulation ◽  
High Sensitivity ◽  
Rapid Screening ◽  
Osmotic Gradient ◽  
Physiological Processes ◽  
High Throughput Drug Screening ◽  
Microfluidic Chamber ◽  
Pharmaceutical Agents

ABSTRACTThe maintenance of cell volume is critical to health. Cell volume change reflects many biological and physiological processes. We have developed a lab-chip to measure cell volume change in real-time with high sensitivity and resolution, and applicable to both adherent and suspended cell populations. The volume change was detected by measuring the impedance of extra-cellular solution within a microfluidic chamber containing the cells. Using microfabrication to make precise chamber dimensions, volume change can be detected in response to an osmotic gradient <1mOsm. The sensor provides rapid screening of pharmaceutical agents affecting cell volume. We have screened for peptides that affect cell volume regulation and found one in spider venom that inhibits at ∼100pM.

Developmentally regulated cell cycle dependence of swelling-activated anion channel activity in the mouse embryo

Development ◽  
2001 ◽  
Vol 128 (18) ◽  
pp. 3427-3434 ◽  
Author(s):  
Marika Kolajova ◽  
Mary-Anne Hammer ◽  
Jennifer L. Collins ◽  
Jay M. Baltz
Keyword(s):  
Cell Cycle ◽  
Cell Volume ◽  
Cell Volume Regulation ◽  
Germinal Vesicle ◽  
Anion Channel ◽  
Mouse Embryos ◽  
Organic Osmolytes ◽  
Developmentally Regulated ◽  
Cell Stage ◽  
Cycle Dependent

Anion channels activated by increased cell volume are a nearly ubiquitous mechanism of cell volume regulation, including in early preimplantation mouse embryos. Here, we show that the swelling-activated anion current (ICl,swell) in early mouse embryos is cell-cycle dependent, and also that this dependence is developmentally regulated. ICl,swell is present both in first meiotic prophase (germinal vesicle stage) mouse oocytes and in unfertilized mature oocytes in second meiotic metaphase, and it persists after fertilization though the 1-cell and 2-cell stages. ICl,swell was found to remain unchanged during metaphase at the end of the 1-cell stage. However, ICl,swell decreased during prophase and became nearly undetectable upon entry into metaphase at the end of the 2-cell stage. Entry into prophase/metaphase was required for the decrease in ICl,swell at the end of the 2-cell stage, since it persisted indefinitely in 2-cell embryos arrested in late G2. There is considerable evidence that the channel underlying ICl,swell is not only permeable to inorganic anions, but to organic osmolytes as well. We found a similar pattern of cell cycle and developmental dependence in the 1-cell and 2-cell stages for the swelling-induced increase in permeability to the organic osmolyte glycine. Thus, entry into metaphase deactivates ICl,swell in embryos, but only after developmental progression through the 2-cell stage.

scholarly journals PDLIM1: Structure, function and implication in cancer

Cell Stress ◽  
2021 ◽  
Vol 5 (8) ◽  
pp. 119-127
Author(s):  
Jian-Kang Zhou ◽  
Xin Fan ◽  
Jian Cheng ◽  
Wenrong Liu ◽  
Yong Peng
Keyword(s):  
Structure Function ◽  
Synapse Formation ◽  
Protein Complexes ◽  
Structure And Function ◽  
Cytoskeletal Protein ◽  
Tumor Initiation ◽  
Human Cancers ◽  
Physiological Processes ◽  
And Function

PDLIM1, a member of the PDZ-LIM family, is a cytoskeletal protein and functions as a platform to form distinct protein complexes, thus participating in multiple physiological processes such as cytoskeleton regulation and synapse formation. Emerging evidence demonstrates that PDLIM1 is dysregualted in a variety of tumors and plays essential roles in tumor initiation and progression. In this review, we summarize the structure and function of PDLIM1, as well as its important roles in human cancers.

Sign in / Sign up

Export Citation Format

Share Document