scholarly journals Cell Volume-Activated and Volume-Correlated Anion Channels in Mammalian Cells: Their Biophysical, Molecular, and Pharmacological Properties

2018 ◽  
Vol 71 (1) ◽  
pp. 49-88 ◽  
Author(s):  
Yasunobu Okada ◽  
Toshiaki Okada ◽  
Kaori Sato-Numata ◽  
Md. Rafiqul Islam ◽  
Yuhko Ando-Akatsuka ◽  
...  
Keyword(s):  
Cell Volume ◽  
Mammalian Cells ◽  
Pharmacological Properties ◽  
Anion Channels

scholarly journals Hydrogen, Bicarbonate, and Their Associated Exchangers in Cell Volume Regulation

2021 ◽  
Vol 9 ◽  
Author(s):  
Yizeng Li ◽  
Xiaohan Zhou ◽  
Sean X. Sun
Keyword(s):  
Ion Channels ◽  
Cell Volume ◽  
Volume Regulation ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Water Flux ◽  
Cell Volume Regulation ◽  
Sodium Potassium ◽  
Before And After

Cells lacking a stiff cell wall, e.g., mammalian cells, must actively regulate their volume to maintain proper cell function. On the time scale that protein production is negligible, water flow in and out of the cell determines the cell volume variation. Water flux follows hydraulic and osmotic gradients; the latter is generated by various ion channels, transporters, and pumps in the cell membrane. Compared to the widely studied roles of sodium, potassium, and chloride in cell volume regulation, the effects of proton and bicarbonate are less understood. In this work, we use mathematical models to analyze how proton and bicarbonate, combined with sodium, potassium, chloride, and buffer species, regulate cell volume upon inhibition of ion channels, transporters, and pumps. The model includes several common, widely expressed ion transporters and focuses on obtaining generic outcomes. Results show that the intracellular osmolarity remains almost constant before and after cell volume change. The steady-state cell volume does not depend on water permeability. In addition, to ensure the stability of cell volume and ion concentrations, cells need to develop redundant mechanisms to maintain homeostasis, i.e., multiple ion channels or transporters are involved in the flux of the same ion species. These results provide insights for molecular mechanisms of cell volume regulation with additional implications for water-driven cell migration.

scholarly journals Multivalent proteins rapidly and reversibly phase-separate upon osmotic cell volume change

2019 ◽  
Author(s):  
Ameya P. Jalihal ◽  
Sethuramasundaram Pitchiaya ◽  
Lanbo Xiao ◽  
Pushpinder Bawa ◽  
Xia Jiang ◽  
...  
Keyword(s):  
Phase Separation ◽  
Cell Volume ◽  
Volume Change ◽  
Mammalian Cells ◽  
Internal State ◽  
Transcription Termination ◽  
Cell Types ◽  
List Type ◽  
Molecular Crowding ◽  
Minimal Impact

SUMMARYProcessing bodies (PBs) and stress granules (SGs) are prominent examples of sub-cellular, membrane-less compartments that are observed under physiological and stress conditions, respectively. We observe that the trimeric PB protein DCP1A rapidly (within ∼10 s) phase-separates in mammalian cells during hyperosmotic stress and dissolves upon isosmotic rescue (over ∼100 s) with minimal impact on cell viability even after multiple cycles of osmotic perturbation. Strikingly, this rapid intracellular hyperosmotic phase separation (HOPS) correlates with the degree of cell volume compression, distinct from SG assembly, and is exhibited broadly by homo-multimeric (valency ≥ 2) proteins across several cell types. Notably, HOPS sequesters pre-mRNA cleavage factor components from actively transcribing genomic loci, providing a mechanism for hyperosmolarity-induced global impairment of transcription termination. Together, our data suggest that the multimeric proteome rapidly responds to changes in hydration and molecular crowding, revealing an unexpected mode of globally programmed phase separation and sequestration that adapts the cell to volume change.GRAPHICAL ABSTRACTIN BRIEFCells constantly experience osmotic variation. These external changes lead to changes in cell volume, and consequently the internal state of molecular crowding. Here, Jalihal and Pitchiaya et al. show that multimeric proteins respond rapidly to such cellular changes by undergoing rapid and reversible phase separation.HIGHLIGHTSDCP1A undergoes rapid and reversible hyperosmotic phase separation (HOPS)HOPS of DCP1A depends on its trimerization domainSelf-interacting multivalent proteins (valency ≥ 2) undergo HOPSHOPS of CPSF6 explains transcription termination defects during osmotic stress

Physiological significance of volume-regulatory transporters

1999 ◽  
Vol 276 (5) ◽  
pp. C995-C1011 ◽  
Author(s):  
W. Charles O’Neill
Keyword(s):  
Cell Volume ◽  
Volume Regulation ◽  
Mammalian Cells ◽  
Ion Transporters ◽  
Subsequent Growth ◽  
The Past ◽  
Shrinkage And Swelling ◽  
Acute Changes

Research over the past 25 years has identified specific ion transporters and channels that are activated by acute changes in cell volume and that serve to restore steady-state volume. The mechanism by which cells sense changes in cell volume and activate the appropriate transporters remains a mystery, but recent studies are providing important clues. A curious aspect of volume regulation in mammalian cells is that it is often absent or incomplete in anisosmotic media, whereas complete volume regulation is observed with isosmotic shrinkage and swelling. The basis for this may lie in an important role of intracellular Cl− in controlling volume-regulatory transporters. This is physiologically relevant, since the principal threat to cell volume in vivo is not changes in extracellular osmolarity but rather changes in the cellular content of osmotically active molecules. Volume-regulatory transporters are also closely linked to cell growth and metabolism, producing requisite changes in cell volume that may also signal subsequent growth and metabolic events. Thus, despite the relatively constant osmolarity in mammals, volume-regulatory transporters have important roles in mammalian physiology.

scholarly journals Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance

Channels ◽  
2015 ◽  
Vol 9 (6) ◽  
pp. 380-396 ◽  
Author(s):  
Else K Hoffmann ◽  
Belinda H Sørensen ◽  
Daniel P R Sauter ◽  
Ian H Lambert
Keyword(s):  
Drug Resistance ◽  
Cell Volume ◽  
Anion Channels

scholarly journals A Serine Residue in ClC-3 Links Phosphorylation–Dephosphorylation to Chloride Channel Regulation by Cell Volume

1999 ◽  
Vol 113 (1) ◽  
pp. 57-70 ◽  
Author(s):  
Dayue Duan ◽  
Suzanne Cowley ◽  
Burton Horowitz ◽  
Joseph R. Hume
Keyword(s):  
Cell Volume ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Phosphorylation Site ◽  
Cardiac Cells ◽  
Site Directed Mutagenesis ◽  
Cell Swelling ◽  
Transport Systems ◽  
Serine Residue ◽  
Channel Regulation

In many mammalian cells, ClC-3 volume-regulated chloride channels maintain a variety of normal cellular functions during osmotic perturbation. The molecular mechanisms of channel regulation by cell volume, however, are unknown. Since a number of recent studies point to the involvement of protein phosphorylation/dephosphorylation in the control of volume-regulated ionic transport systems, we studied the relationship between channel phosphorylation and volume regulation of ClC-3 channels using site-directed mutagenesis and patch-clamp techniques. In native cardiac cells and when overexpressed in NIH/3T3 cells, ClC-3 channels were opened by cell swelling or inhibition of endogenous PKC, but closed by PKC activation, phosphatase inhibition, or elevation of intracellular Ca2+. Site-specific mutational studies indicate that a serine residue (serine51) within a consensus PKC-phosphorylation site in the intracellular amino terminus of the ClC-3 channel protein represents an important volume sensor of the channel. These results provide direct molecular and pharmacological evidence indicating that channel phosphorylation/dephosphorylation plays a crucial role in the regulation of volume sensitivity of recombinant ClC-3 channels and their native counterpart, ICl.vol.

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 Generation of WNK1 knockout cell lines by CRISPR/Cas-mediated genome editing

2015 ◽  
Vol 308 (4) ◽  
pp. F366-F376 ◽  
Author(s):  
Ankita Roy ◽  
Joshua H. Goodman ◽  
Gulnaz Begum ◽  
Bridget F. Donnelly ◽  
Gabrielle Pittman ◽  
...  
Keyword(s):  
Cell Volume ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Cell Volume Regulation ◽  
Fluid Secretion ◽  
Salt Transport ◽  
Simple Method ◽  
Knock Out ◽  
Hypertonic Stress ◽  
Wnk Kinases

Sodium-coupled SLC12 cation chloride cotransporters play important roles in cell volume and chloride homeostasis, epithelial fluid secretion, and renal tubular salt reabsorption. These cotransporters are phosphorylated and activated indirectly by With-No-Lysine (WNK) kinases through their downstream effector kinases, Ste20- and SPS1-related proline alanine-rich kinase (SPAK) and oxidative stress-responsive kinase 1 (OSR1). Multiple WNK kinases can coexist within a single cell type, although their relative contributions to SPAK/OSR1 activation and salt transport remain incompletely understood. Deletion of specific WNKs from cells that natively express a functional WNK-SPAK/OSR1 network will help resolve these knowledge gaps. Here, we outline a simple method to selectively knock out full-length WNK1 expression from mammalian cells using RNA-guided clustered regularly interspaced short palindromic repeats/Cas9 endonucleases. Two clonal cell lines were generated by using a single-guide RNA (sgRNA) targeting exon 1 of the WNK1 gene, which produced indels that abolished WNK1 protein expression. Both cell lines exhibited reduced endogenous WNK4 protein abundance, indicating that WNK1 is required for WNK4 stability. Consistent with an on-target effect, the reduced WNK4 abundance was associated with increased expression of the KLHL3/cullin-3 E3 ubiquitin ligase complex and was rescued by exogenous WNK1 overexpression. Although the morphology of the knockout cells was indistinguishable from control, they exhibited low baseline SPAK/OSR1 activity and failed to trigger regulatory volume increase after hypertonic stress, confirming an essential role for WNK1 in cell volume regulation. Collectively, our data show how this new, powerful, and accessible gene-editing technology can be used to dissect and analyze WNK signaling networks.

scholarly journals Alanine uptake activates hepatocellular chloride channels

1997 ◽  
Vol 273 (4) ◽  
pp. G849-G853 ◽  
Author(s):  
Steven D. Lidofsky ◽  
Richard M. Roman
Keyword(s):  
Amino Acid ◽  
Mammalian Cells ◽  
Chloride Channels ◽  
Amino Acid Uptake ◽  
Experimental Models ◽  
Cell Swelling ◽  
Acid Uptake ◽  
Adaptive Responses ◽  
Anion Channels

Cells involved in the retrieval and metabolic conversion of amino acids undergo significant increases in size in response to amino acid uptake. The resultant adaptive responses to cell swelling are thought to include increases in membrane K+ and Cl− permeability through activation of volume-sensitive ion channels. This viewpoint is largely based on experimental models of hypotonic swelling, but few mammalian cells experience hypotonic challenge in vivo. Here we have examined volume regulatory responses in a physiological model of cell-swelling alanine uptake in immortalized hepatocytes. Alanine-induced cell swelling was followed by a decrease in cell volume that was temporally associated with an increase in membrane Cl− currents. These currents were dependent both on alanine concentration and Na+, suggesting that currents were stimulated by Na+-coupled alanine uptake. Cl− currents were outwardly rectifying, exhibited an anion permeability sequence of I− > Br− > Cl−, and were inhibited by the Cl− channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid, features similar to those reported for a widely distributed class of volume-sensitive anion channels evoked by experimental hypotonic stress. These findings suggest that volume-sensitive anion channels participate in adaptive responses to amino acid uptake and provide such channels with a new physiological context.

Cellular and molecular physiology of volume-sensitive anion channels

1996 ◽  
Vol 270 (3) ◽  
pp. C711-C730 ◽  
Author(s):  
K. Strange ◽  
F. Emma ◽  
P. S. Jackson
Keyword(s):  
Cell Volume ◽  
Metabolic Pathways ◽  
Anion Channels ◽  
Animal Cells ◽  
Molecular Physiology ◽  
Solute Content ◽  
Homeostatic Process ◽  
Different Types ◽  
The Face ◽  
Constant Cell

Maintenance of a constant cell volume in the face of osmotic stress is an evolutionarily ancient homeostatic process. Over the last two decades physiologists have gained an impressive understanding of the "volume-sensitive" channels, cotransporters, exchangers, metabolic pathways, and genes that are responsible for modulating intracellular solute content and cell volume. This review focuses on one part of this story, the characteristics and osmoregulatory functions of volume-sensitive anion channels. Three distinct types of swelling-activated anion channels have been observed and studied extensively in animal cells. These channels include 1) ClC-2, which is a member of the ClC family of voltage-gated anion channels, 2) an outwardly rectifying intermediate conductance channel, and 3) a large-conductance or "maxi" channel. In addition to these three channels, several other less well-characterized anion channels have been observed. This review discusses the electrophysiological and molecular biological characteristics and regulation of these channels. The possible roles different types of anion channels might play in cell volume homeostasis are also discussed.

Involvements of the ABC protein ABCF2 and α-actinin-4 in regulation of cell volume and anion channels in human epithelial cells

2012 ◽  
Vol 227 (10) ◽  
pp. 3498-3510 ◽  
Author(s):  
Yuhko Ando-Akatsuka ◽  
Takahiro Shimizu ◽  
Tomohiro Numata ◽  
Yasunobu Okada
Keyword(s):  
Epithelial Cells ◽  
Cell Volume ◽  
Anion Channels ◽  
Abc Protein ◽  
Human Epithelial Cells
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