scholarly journals From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

2021 ◽  
Vol 9 ◽  
Author(s):  
Markus Ritter ◽  
Nikolaus Bresgen ◽  
Hubert H. Kerschbaum
Keyword(s):  
Cell Death ◽  
Cell Volume ◽  
Volume Regulation ◽  
Cell Volume Regulation ◽  
Extracellular Fluid ◽  
Cell Swelling ◽  
Cellular Mechanisms ◽  
Vesicle Membrane ◽  
Membrane Area ◽  
A Cell

The volumes of a cell [cell volume (CV)] and its organelles are adjusted by osmoregulatory processes. During pinocytosis, extracellular fluid volume equivalent to its CV is incorporated within an hour and membrane area equivalent to the cell’s surface within 30 min. Since neither fluid uptake nor membrane consumption leads to swelling or shrinkage, cells must be equipped with potent volume regulatory mechanisms. Normally, cells respond to outwardly or inwardly directed osmotic gradients by a volume decrease and increase, respectively, i.e., they shrink or swell but then try to recover their CV. However, when a cell death (CD) pathway is triggered, CV persistently decreases in isotonic conditions in apoptosis and it increases in necrosis. One type of CD associated with cell swelling is due to a dysfunctional pinocytosis. Methuosis, a non-apoptotic CD phenotype, occurs when cells accumulate too much fluid by macropinocytosis. In contrast to functional pinocytosis, in methuosis, macropinosomes neither recycle nor fuse with lysosomes but with each other to form giant vacuoles, which finally cause rupture of the plasma membrane (PM). Understanding methuosis longs for the understanding of the ionic mechanisms of cell volume regulation (CVR) and vesicular volume regulation (VVR). In nascent macropinosomes, ion channels and transporters are derived from the PM. Along trafficking from the PM to the perinuclear area, the equipment of channels and transporters of the vesicle membrane changes by retrieval, addition, and recycling from and back to the PM, causing profound changes in vesicular ion concentrations, acidification, and—most importantly—shrinkage of the macropinosome, which is indispensable for its proper targeting and cargo processing. In this review, we discuss ion and water transport mechanisms with respect to CVR and VVR and with special emphasis on pinocytosis and methuosis. We describe various aspects of the complex mutual interplay between extracellular and intracellular ions and ion gradients, the PM and vesicular membrane, phosphoinositides, monomeric G proteins and their targets, as well as the submembranous cytoskeleton. Our aim is to highlight important cellular mechanisms, components, and processes that may lead to methuotic CD upon their derangement.

scholarly journals Cell Death Induction and Protection by Activation of Ubiquitously Expressed Anion/Cation Channels. Part 1: Roles of VSOR/VRAC in Cell Volume Regulation, Release of Double-Edged Signals and Apoptotic/Necrotic Cell Death

2021 ◽  
Vol 8 ◽  
Author(s):  
Yasunobu Okada ◽  
Ravshan Z. Sabirov ◽  
Kaori Sato-Numata ◽  
Tomohiro Numata
Keyword(s):  
Cell Death ◽  
Cell Volume ◽  
Volume Regulation ◽  
Cell Volume Regulation ◽  
Cell Swelling ◽  
Cation Channels ◽  
Necrotic Cell Death ◽  
Anion Channels ◽  
Necrotic Cell ◽  
Regulated Necrosis

Cell volume regulation (CVR) is essential for survival and functions of animal cells. Actually, normotonic cell shrinkage and swelling are coupled to apoptotic and necrotic cell death and thus called the apoptotic volume decrease (AVD) and the necrotic volume increase (NVI), respectively. A number of ubiquitously expressed anion and cation channels are involved not only in CVD 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. The Part 1 focuses on the roles of the volume-sensitive outwardly rectifying anion channels (VSOR), also called the volume-regulated anion channel (VRAC), which is activated by cell swelling or reactive oxygen species (ROS) in a manner dependent on intracellular ATP. First we describe phenotypical properties, the molecular identity, and physical pore dimensions of VSOR/VRAC. Second, we highlight the roles of VSOR/VRAC in the release of organic signaling molecules, such as glutamate, glutathione, ATP and cGAMP, that play roles as double-edged swords in cell survival. Third, we discuss how VSOR/VRAC is involved in CVR and cell volume dysregulation as well as in the induction of or protection from apoptosis, necrosis and regulated necrosis under pathophysiological conditions.

Dihydropyridine-sensitive cell volume regulation in proximal tubule: the calcium window

1990 ◽  
Vol 259 (6) ◽  
pp. F950-F960 ◽  
Author(s):  
N. A. McCarty ◽  
R. G. O'Neil
Keyword(s):  
Cell Volume ◽  
Volume Regulation ◽  
Regulatory Volume Decrease ◽  
Cell Volume Regulation ◽  
Cell Swelling ◽  
Channel Blockers ◽  
Ca Channel ◽  
Hypotonic Solution ◽  
Dependent Manner ◽  
Intracellular Ca

The mechanism underlying the activation of hypotonic cell volume regulation was studied in rabbit proximal straight tubule (PST). When isolated non-perfused tubules were exposed to hypotonic solution, cells swelled rapidly and then underwent a regulatory volume decrease (RVD). The extent of regulation after swelling was highly dependent on extracellular Ca concentration ([Ca2+]o), with a half-maximal inhibition (K1/2) for [Ca2+]o of approximately 100 microM. RVD was blocked by the Ca-channel blockers verapamil, lanthanum, and the dihydropyridines (DHP) nifedipine and nitrendipine, implicating voltage-activated Ca channels in the RVD response. Using the fura-2 fluorescence-ratio technique, we observed that cell swelling caused a sustained rise in intracellular Ca ([Ca2+]i) only when [Ca2+]o was normal (1 mM) but not when [Ca2+]o was low (1-10 microM). Furthermore, external Ca was required early on during swelling to induce RVD. If RVD was initially blocked by reducing [Ca2+]o or by addition of verapamil during hypotonic swelling, volume regulation could only be restored by subsequently inducing Ca entry within the first 1 min or less of exposure to hypotonic solution. These data indicate a "calcium window" of less than 1 min, during which RVD is sensitive to Ca, and that part of the Ca-dependent mechanism responsible for achieving RVD undergoes inactivation after swelling. It is concluded that RVD in rabbit PST is modulated by Ca via a DHP-sensitive mechanism in a time-dependent manner.

scholarly journals Interactions of sodium transport, cell volume, and calcium in frog urinary bladder.

1987 ◽  
Vol 89 (5) ◽  
pp. 687-702 ◽  
Author(s):  
C W Davis ◽  
A L Finn
Keyword(s):  
Cell Volume ◽  
Volume Regulation ◽  
Apical Membrane ◽  
Basolateral Membrane ◽  
Cell Volume Regulation ◽  
Positive Control ◽  
Negative Control ◽  
Cell Swelling ◽  
Ionophore A23187 ◽  
Intracellular Ca

The volume of individual cells in intact frog urinary bladders was determined by quantitative microscopy and changes in volume were used to monitor the movement of solute across the basolateral membrane. When exposed to a serosal hyposmotic solution, the cells swell as expected for an osmometer, but then regulate their volume back to near control in a process that involves the loss of KCl. We show here that volume regulation is abolished by Ba++, which suggests that KCl movements are mediated by conductive channels for both ions. Volume regulation is also inhibited by removing Ca++ from the serosal perfusate, which suggests that the channels are activated by this cation. Previously, amiloride was observed to inhibit volume regulation: in this study, amiloride-inhibited, hyposmotically swollen cells lost volume when the Ca++ ionophore A23187 was added to Ca++-replete media. We attempted to effect volume changes under isosmotic conditions by suddenly inhibiting Na+ entry across the apical membrane with amiloride, or Na+ exit across the basolateral membrane with ouabain. Neither of these Na+ transport inhibitors produced the expected results. Amiloride, instead of causing a decrease in cell volume, had no effect, and ouabain, instead of causing cell swelling, caused cell shrinkage. However, increasing cell Ca++ with A23187, in both the absence and presence of amiloride, caused cells to lose volume, and Ca++-free Ringer's solution (serosal perfusate only) caused ouabain-blocked cells to swell. Finally, again under isosmotic conditions, removal of Na+ from the serosal perfusate caused a loss of volume from cells exposed to amiloride. These results strongly suggest that intracellular Ca++ mediates cell volume regulation by exerting a negative control on apical membrane Na+ permeability and a positive control on basolateral membrane K+ permeability. They also are compatible with the existence of a basolateral Na+/Ca++ exchanger.

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.

Potassium-induced cell swelling in Necturus gallbladder epithelium

1988 ◽  
Vol 254 (5) ◽  
pp. C643-C650 ◽  
Author(s):  
C. W. Davis ◽  
A. L. Finn
Keyword(s):  
Cell Volume ◽  
Volume Regulation ◽  
Basolateral Membrane ◽  
Cell Volume Regulation ◽  
Cell Swelling ◽  
Gallbladder Epithelium ◽  
Bathing Medium ◽  
Necturus Gallbladder ◽  
Per Se ◽  
Cl Conductance

In Necturus gallbladder epithelium, elevation of mucosal K+ to 95 mM in the presence of 10 mM Na+ resulted in cell swelling at a rate of 3.2% original volume per minute, followed by volume-regulatory shrinking. When Na+ was completely removed from or when amiloride (10(-4) M) was added to the mucosal medium, K+-induced cell swelling was abolished. In the presence of 10 mM Na+, 1 mM Ba2+ abolished and substitution of mucosal Cl- by NO-3 had no effect on K+-induced swelling. Thus solute entry following elevation of mucosal K+ is effected by separate K+ and Cl- pathways. Furthermore, substitution of 95 mM K+ for Na+ in the mucosal bathing medium leads to the development of a Cl- conductance in the basolateral membrane as long as some Na+ remains in the medium. However, cell swelling induced by mucosal dilution does not lead to the appearance of a Cl- conductance. Thus the activation of this conductance requires both swelling and membrane depolarization. These results show that 1) high mucosal K+ leads to cell swelling due to the entry of Cl- along with K+ and the Cl- can enter across either membrane, 2) the Cl- pathways require the presence of mucosal Na+, and 3) cell volume regulation is activated by an increase in volume per se, i.e., a hyposmotic exposure is not required for volume regulation to occur.

scholarly journals Indirect Role of AQP4b and AQP4d Isoforms in Dynamics of Astrocyte Volume and Orthogonal Arrays of Particles

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 735 ◽  
Author(s):  
Marjeta Lisjak ◽  
Maja Potokar ◽  
Robert Zorec ◽  
Jernej Jorgačevski
Keyword(s):  
Plasma Membrane ◽  
Cell Volume ◽  
Volume Regulation ◽  
Water Channel ◽  
Regulatory Volume Decrease ◽  
Cell Volume Regulation ◽  
Orthogonal Arrays ◽  
Cell Swelling ◽  
Early Endosomes ◽  
Orthogonal Arrays Of Particles

Water channel aquaporin 4 (AQP4) plays a key role in the regulation of water homeostasis in the central nervous system (CNS). It is predominantly expressed in astrocytes lining blood–brain and blood–liquor boundaries. AQP4a (M1), AQP4c (M23), and AQP4e, present in the plasma membrane, participate in the cell volume regulation of astrocytes. The function of their splicing variants, AQP4b and AQP4d, predicted to be present in the cytoplasm, is unknown. We examined the cellular distribution of AQP4b and AQP4d in primary rat astrocytes and their role in cell volume regulation. The AQP4b and AQP4d isoforms exhibited extensive cytoplasmic localization in early and late endosomes/lysosomes and in the Golgi apparatus. Neither isoform localized to orthogonal arrays of particles (OAPs) in the plasma membrane. The overexpression of AQP4b and AQP4d isoforms in isoosmotic conditions reduced the density of OAPs; in hypoosmotic conditions, they remained absent from OAPs. In hypoosmotic conditions, the AQP4d isoform was significantly redistributed to early endosomes, which correlated with the increased trafficking of AQP4-laden vesicles. The overexpression of AQP4d facilitated the kinetics of cell swelling, without affecting the regulatory volume decrease. Therefore, although they reside in the cytoplasm, AQP4b and AQP4d isoforms may play an indirect role in astrocyte volume changes.

TAURINE TRANSPORT CHARACTERISTICS OF THE EMBRYONIC SKATE (RAJA EGLANTERIA) HEART

1993 ◽  
Vol 182 (1) ◽  
pp. 291-295
Author(s):  
L. Goldstein ◽  
C. A. Luer ◽  
P. C. Blum
Keyword(s):  
Amino Acid ◽  
Cell Volume ◽  
Volume Regulation ◽  
Cell Volume Regulation ◽  
Extracellular Fluid ◽  
Beta Alanine ◽  
Hypotonic Stress ◽  
High Concentrations ◽  
Clearnose Skate ◽  
Raja Eglanteria

The hearts of elasmobranchs, like those of other vertebrates, accumulate high concentrations of the amino acid taurine (Boyd et al. 1977), which is used to maintain osmotic equilibrium with the extracellular fluid. We recently demonstrated that embryonic hearts of the clearnose skate (Raja eglanteria Bosc) were able to accumulate taurine equally as well as hearts of adult skates and, as in adults, the accumulation was the result of transport from extracellular taurine across the cell membrane against a steep concentration gradient (Goldstein et al. 1990). In adult skate hearts, the uptake of taurine is Na+-dependent and competitively inhibited by beta-alanine (Forster and Hannafin, 1980a), indicating that transport occurs by the beta-amino acid system found in many vertebrate hearts (Huxtable, 1992). During hypotonic stress, adult skate hearts release taurine and other amino acids. The Na+/taurine cotransport system permits the skate heart to maintain high concentrations of intracellular taurine, while the hypotonicity-activated taurine release aids in cell volume regulation following dilution of the extracellular fluid. The aims of the present study were to determine whether taurine uptake in the embryonic skate heart is Na+-dependent as in the adult and whether the skate heart has the capability of cell volume regulation (during hypotonic stress) before hatching.

scholarly journals Acid- and Volume-Sensitive Chloride Currents in Microglial Cells

2019 ◽  
Vol 20 (14) ◽  
pp. 3475 ◽  
Author(s):  
Michael Kittl ◽  
Katharina Helm ◽  
Marlena Beyreis ◽  
Christian Mayr ◽  
Martin Gaisberger ◽  
...  
Keyword(s):  
Cell Volume ◽  
Volume Regulation ◽  
Regulatory Volume Decrease ◽  
Cell Volume Regulation ◽  
Cell Types ◽  
Microglial Cells ◽  
Cell Swelling ◽  
Mean Cell Volume ◽  
Current Activation ◽  
And Migration

Many cell types express an acid-sensitive outwardly rectifying (ASOR) anion current of an unknown function. We characterized such a current in BV-2 microglial cells and then studied its interrelation with the volume-sensitive outwardly rectifying (VSOR) Cl− current and the effect of acidosis on cell volume regulation. We used patch clamp, the Coulter method, and the pH-sensitive dye BCECF to measure Cl− currents and cell membrane potentials, mean cell volume, and intracellular pH, respectively. The ASOR current activated at pH ≤ 5.0 and displayed an I− > Cl− > gluconate− permeability sequence. When compared to the VSOR current, it was similarly sensitive to DIDS, but less sensitive to DCPIB, and insensitive to tamoxifen. Under acidic conditions, the ASOR current was the dominating Cl− conductance, while the VSOR current was apparently inactivated. Acidification caused cell swelling under isotonic conditions and prevented the regulatory volume decrease under hypotonicity. We conclude that acidification, associated with activation of the ASOR- and inactivation of the VSOR current, massively impairs cell volume homeostasis. ASOR current activation could affect microglial function under acidotoxic conditions, since acidosis is a hallmark of pathophysiological events like inflammation, stroke or ischemia and migration and phagocytosis in microglial cells are closely related to cell volume regulation.

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