Figure - uploaded by Valentina E Yurinskaya
Content may be subject to copyright.
Changes in the permeability coefficients of Na + , K + , and Cl − channels obtained for apoptotic U937 cells by computation at a different set of parameters of NC, KC, and NKCC cotransporters (cells A in Table 2).
Source publication
Fluxes of monovalent ions through the multiple pathways of the plasma membrane are highly interdependent, and their assessment by direct measurement is difficult or even impossible. Computation of the entire flux balance helps to identify partial flows and study the functional expression of individual transporters. Our previous computation of unidi...
Context in source publication
Context 1
... in pCl, pK, and pNa, which give good agreement between the calculated and observed dynamics of the ion and water content during apoptosis, turn out to be practically the same (qualitatively) as in the cell without NKCC and KC in A-X cells, but with more significant changes in pCl (B) Additional changes in channel permeability shown on the top graphs: pna 0.00215 t= 0 →0.0015 t> 0 ; pcl 0.005 t= 0 →0.09 t> 0 ; pk 0.0058 t= 0 →0.0174 t> 0 ; inc, ikc, and inkcc rate coefficients remain constant throughout. Initial parameters: na0 140; k0 5.8; cl0 116; B0 48.2; kv 1.0; na 32; k 117; cl 40; beta 0.029; gamma 1.50; pna 0.00215; pk 0.0058; pcl 0.005; inc 2.8E-5; ikc 8. 8E-5; and inkcc 8E-10. in A-Y cells ( Table 5). The experimental data obtained for the studied U937 cells do not allow one to accurately determine the changes in parameter values but are sufficient to determine the extent of possible parameter changes. ...Similar publications
Studying the transport of monovalent ions across the cell membrane in living cells is complicated by the strong interdependence of fluxes through parallel pathways and requires therefore computational analysis of the entire electrochemical system of the cell. Current paper shows how to calculate changes in the cell water balance and ion fluxes caus...
Recently, we have developed software that allows, using a minimum of required experimental data, to find the characteristics of ion homeostasis and a list of all unidirectional fluxes of monovalent ions through the main pathways in the cell membrane both in a balanced state and during the transient processes. Our approach has been successfully vali...
Citations
... There is a range of models for the NKA from a simple constant model to complex nonlinear models (Garay and Garrahan, 1973;Smith and Crampin, 2004;Keener and Sneyd, 2009;Yurinskaya et al., 2020). We will show that the mathematical form of these models does not affect the steady-state of a cell, and therefore, considering a constant rate model for the NKA pump suffices. ...
... As the figure shows, the steady-state values coincide exactly. We observed that this also occurs for less complicated nonlinear dynamics such as p NKA[ Na + ] i (Yurinskaya et al., 2020;Keener and Sneyd, 2009) ...
The presence of impermeant molecules within a cell can lead to an increase in cell volume through the influx of water driven by osmosis. This phenomenon is known as the Donnan (or Gibbs–Donnan) effect. Animal cells actively transport ions to counteract the Donnan effect and regulate their volume, actively pumping Na⁺ out and K⁺ into their cytosol using the Na⁺/K⁺ ATPase (NKA) pump. The pump-leak equations (PLEs) are a system of algebraic-differential equations to model the membrane potential, ion (Na⁺, K⁺, and Cl⁻), and water flux across the cell membrane, which provide insight into how the combination of passive ions fluxes and active transport contribute to stabilizing cell volume. Our broad objective is to provide analytical insight into the PLEs through three lines of investigation: (1) we show that the provision of impermeant extracellular molecules can stabilize the volume of a passive cell; (2) we demonstrate that the mathematical form of the NKA pump is not as important as the stoichiometry for cell stabilization; and (3) we investigate the interaction between the NKA pump and cation–chloride co-transporters (CCCs) on cell stabilization, showing that NCC can destabilize a cell while NKCC and KCC can stabilize it. We incorporate extracellular impermeant molecules, NKA pump, and CCCs into the PLEs and derive the exact formula for the steady states in terms of all the parameters. This analytical expression enables us to easily explore the effect of each of the system parameters on the existence and stability of the steady states.
... The pump transports three sodium ions outside and two potassium ions inside the cell, with the use of ATP [24]. The research conducted by Yurinskaya et al. show that the imbalance of activity of Na + /K + pump induces membrane shrinkage, which leads to apoptosis [25]. In our study, the imbalance of sodium and potassium concentrations in cells treated with elements used alone and in combinations was observed. ...
The elements are present in the environment. Moreover, they are used in pharmacy and the production of new materials used in medical applications. They are often as environmental pollutants. They can accumulate in organisms and induce toxic effects on the cellular level. HepG2, L 929 and Caco-2 cell lines were exposed to known concentrations of chromium chloride, iron chloride, nickel chloride, molybdenum trioxide and cobalt chloride (200 or 1000 μ M used alone and in combinations). Concentrations of chromium, iron, nickel, molybdenum and cobalt in the cell lysate and the culture medium were determined by ICP-MS. Moreover, sodium, potassium, calcium and magnesium concentrations were also measured. What is more, cells were observed under light and scanning electron microscope. The dose-dependent increase in the concentration of chromium, iron, nickel, molybdenum and cobalt in all cell lines after incubation with elements was observed. Potassium concentration decreases while sodium calcium and magnesium increase after incubation of cells with of mentioned elements. The incubation of cells with microelements induces cell morphology changes. The presented study shows the crucial role of tested microelements in the induction of cell death as a result of an imbalance of sodium, potassium, calcium and magnesium concentration inside the cell.
... Our approach is based on the use of the thermodynamic classification of ion transport systems through the cell membrane and does not depend on the mechanism of ion movement. It takes into account all the main types of ion-conducting pathways through the plasma membrane: sodium pump, electrically conductive channels, and all main types of cation-chloride cotransporters [10][11][12][13][14][15]. Until now, the reliability of the proposed description has been successfully shown for transient processes such as Na/K pump blockage by ouabain or replacing extracellular Na + with Li + , as well as in staurosporine-induced apoptosis in proliferating lymphoid U937 cells [10][11][12][13][14]. ...
... It takes into account all the main types of ion-conducting pathways through the plasma membrane: sodium pump, electrically conductive channels, and all main types of cation-chloride cotransporters [10][11][12][13][14][15]. Until now, the reliability of the proposed description has been successfully shown for transient processes such as Na/K pump blockage by ouabain or replacing extracellular Na + with Li + , as well as in staurosporine-induced apoptosis in proliferating lymphoid U937 cells [10][11][12][13][14]. ...
... The TCA precipitates were dissolved in 0.1 N NaOH and analyzed for protein by the Lowry procedure, with serum bovine albumin as a standard. Cell water content was determined by measurements of the buoyant density of the cells in continuous Percoll gradient as described in our previous study [12][13][14][15]. In our experience, measurement of buoyant density of cells is the most sensitive and reliable of all currently existing method for determination of cell water. ...
Recently, we have developed software that allows, using a minimum of required experimental data, to find the characteristics of ion homeostasis and a list of all unidirectional fluxes of monovalent ions through the main pathways in the cell membrane both in a balanced state and during the transient processes. Our approach has been successfully validated in human proliferating lymphoid U937 cells during transient processes after stopping the Na/K pump by ouabain and for staurosporine-induced apoptosis. In present study, we used this approach to find the characteristics of ion homeostasis and the monovalent ion fluxes through the cell membrane of human erythrocytes in a resting state and during the transient processes after stopping the Na/K pump with ouabain and in response to osmotic challenge. Due to their physiological significance, erythrocytes remain the object of numerous studies, both experimental and computational methods. Calculations showed that, under physiological conditions, the K⁺ fluxes through electrodiffusion channels in the entire erythrocyte ion balance is small compared to the fluxes through the Na/K pump and cation–chloride cotransporters. The proposed computer program well predicts the dynamics of the erythrocyte ion balance disorders after stopping the Na/K pump with ouabain. In full accordance with predictions, transient processes in human erythrocytes are much slower than in proliferating cells such as lymphoid U937 cells. Comparison of real changes in the distribution of monovalent ions under osmotic challenge with the calculated ones indicates a change in the parameters of the ion transport pathways through the plasma membrane of erythrocytes in this case. The proposed approach may be useful in studying the mechanisms of various erythrocyte dysfunctions.
... Imaging technology provides the spatiotemporal information of ion dynamics that eludes the aforementioned technologies. Dynamic changes of ion concentrations are the foundation of many important intra-and intercellular processes and reflect cellular responses to environmental perturbations (Leybaert and Sanderson, 2012;Yurinskaya et al., 2020). Measuring these ion concentrations enables inquiry into ion regulation and transportation, therefore tools for such measurements in tissue and whole organisms are of particular interest. ...
Monatomic ions play critical biological roles including maintaining the cellular osmotic pressure, transmitting signals, and catalyzing redox reactions as cofactors in enzymes. The ability to visualize monatomic ion concentration, and dynamic changes in the concentration, is essential to understanding their many biological functions. A growing number of genetically encodable and synthetic indicators enable the visualization and detection of monatomic ions in biological systems. With this review, we aim to provide a survey of the current landscape of reported indicators. We hope this review will be a useful guide to researchers who are interested in using indicators for biological applications and to tool developers seeking opportunities to create new and improved indicators.
... Details of the experimental methods used were described in our previous study [8][9][10]. Briefly, cell water content was estimated by the buoyant density of the cells in continuous Percoll gradient, intracellular K + , Na + and Rb + content was determined by flame emission on a Perkin-Elmer AA 306 spectrophotometer, the intracellular Cl‾ was measured using a radiotracer 36 Cl. ...
... The mathematical model of the movement of monovalent ions across the cell membrane was like that used by Jakobsson [11], and Lew with colleagues [12][13][14], as well as in our previous works [8][9][10]15,16]. It accounts for the Na/K pump, electroconductive channels, cotransporters NC, KC, and NKCC. ...
... The problems in determination of the multiple parameters in a system www.videleaf.com with multiple variables like cell ionic homeostasis are discussed in more detail in [8,9]. Some readers of our previous publications have expressed doubt that using our tool it is possible to obtain a unique set of parameters that provide an agreement between experimental and calculated data. ...
... Details of the experimental methods used were described in our previous study (Yurinskaya et al., 2019;Yurinskaya et al., 2020;Yurinskaya and Vereninov, 2021a). Briefly, cell water content was estimated by the buoyant density of the cells in continuous Percoll gradient, intracellular K + , Na + and Rb + content was determined by flame emission on a Perkin-Elmer AA 306 spectrophotometer, the intracellular Cl‾ was measured using a radiotracer 36 Cl. ...
... The mathematical model of the movement of monovalent ions across the cell membrane was like that used by Jakobsson (1980), and Lew with colleagues (Lew and Bookchin, 1986;Lew et al., 1991;Lew, 2000), as well as in our previous works (Vereninov et al., 2014;Vereninov et al., 2016;Yurinskaya et al., 2019;Yurinskaya et al., 2020;Yurinskaya and Vereninov, 2021a). It accounts for the Na/K pump, electroconductive channels, cotransporters NC, KC, and NKCC. ...
... The algorithm of the numerical solution of the system of these equations is considered in detail in (Vereninov et al., 2014), the using of the executable file is illustrated more in (Yurinskaya et al., 2019). The problems in determination of the multiple parameters in a system with multiple variables like cell ionic homeostasis are discussed in more detail in (Yurinskaya et al., 2019(Yurinskaya et al., , 2020. Some readers of our previous publications have expressed doubt that using our tool it is possible to obtain a unique set of parameters that provide an agreement between experimental and calculated data. ...
Studying the transport of monovalent ions across the cell membrane in living cells is complicated by the strong interdependence of fluxes through parallel pathways and requires therefore computational analysis of the entire electrochemical system of the cell. Current paper shows how to calculate changes in the cell water balance and ion fluxes caused by changes in the membrane channels and transporters during a normal regulatory increase in cell volume in response to osmotic cell shrinkage (RVI) followed by a decrease in cell volume associated with apoptosis (AVD). Our recently developed software is used as a computational analysis tool and the established human lymphoid cells U937 are taken as an example of proliferating animal cells. It is found that, in contrast to countless statements in the literature that cell volume restoration requires the activation of certain ion channels and transporters, the cellular responses such as RVI and AVD can occur in an electrochemical system like U937 cells without any changes in the state of membrane channels or transporters. These responses depend on the types of chloride cotransporters in the membrane and differ in a hyperosmolar medium with additional sucrose and in a medium with additional NaCl. This finding is essential for the identification of the true changes in membrane channels and transporters responsible for RVI and AVD in living cells. It is determined which changes in membrane parameters predicted by computational analysis are consistent with experimental data obtained on living human lymphoid cells U937, Jurkat, and K562 and which are not. An essential part of the results is the developed software that allows researchers without programming experience to calculate the fluxes of monovalent ions via the main transmembrane pathways and electrochemical gradients that move ions across the membrane. The software is available for download. It is useful for studying the functional expression of the channels and transporters in living cells and understanding how the cell electrochemical system works.
... Until now, we tested our tool in prediction of rearrangement of ion homeostasis in U937 cells caused by stopping the Na/K pump using the incomplete model with only NC cotransporter (Vereninov et al., 2014;Yurinskaya et al., 2019). The model with all major types of cotransporters for apoptotic U937 cells was considered in our recent study (Yurinskaya et al., 2020), which showed that the effects of KC and NKCC (well-known cotransporters K-Cl and Na-K-2Cl) are small. The first goal of the present study was to find out whether a model with a full set of cotransporters would be successful in predictions of changes in ion homeostasis after stopping the pump. ...
... The mathematical model of the movement of monovalent ions across the cell membrane was like that used by Jakobsson (1980), Lew and Bookchin (1986), and Lew et al. (1991), as well as in our previous works (Vereninov et al., 2014(Vereninov et al., , 2016Yurinskaya et al., 2019Yurinskaya et al., , 2020. It accounts for the Na/K pump; electroconductive channels; and cotransporters NC, KC, and NKCC. ...
... The algorithm of the numerical solution of the system of these equations is considered in detail in Vereninov et al. (2014), and the use of the executable file is illustrated more in Yurinskaya et al. (2019). The problems in the determination of the multiple parameters in a system with multiple variables like cell ionic homeostasis are discussed in more detail in Yurinskaya et al. (2019Yurinskaya et al. ( , 2020. To use the executable file for the BEZ02BC software, you must open Supplementary Datasheet 1 and execute it according to its text. ...
Cation-coupled chloride cotransporters play a key role in generating the Cl– electrochemical gradient on the cell membrane, which is important for regulation of many cellular processes. However, a quantitative analysis of the interplay between numerous membrane transporters and channels in maintaining cell ionic homeostasis is still undeveloped. Here, we demonstrate a recently developed approach on how to predict cell ionic homeostasis dynamics when stopping the sodium pump in human lymphoid cells U937. The results demonstrate the reliability of the approach and provide the first quantitative description of unidirectional monovalent ion fluxes through the plasma membrane of an animal cell, considering all the main types of cation-coupled chloride cotransporters operating in a system with the sodium pump and electroconductive K+, Na+, and Cl– channels. The same approach was used to study ionic and water balance changes associated with regulatory volume decrease (RVD), a well-known cellular response underlying the adaptation of animal cells to a hypoosmolar environment. A computational analysis of cell as an electrochemical system demonstrates that RVD may happen without any changes in the properties of membrane transporters and channels due to time-dependent changes in electrochemical ion gradients. The proposed approach is applicable when studying truly active regulatory processes mediated by the intracellular signaling network. The developed software can be useful for calculation of the balance of the unidirectional fluxes of monovalent ions across the cell membrane of various cells under various conditions.
Monovalent ions are involved in growth, proliferation, differentiation of cells as well as in their death. This work concerns the ion homeostasis during senescence induction in human mesenchymal endometrium stem cells (hMESC): hMESCs subjected to oxidative stress (pulse H2O2 treatment) enter the premature senescence accompanied by persistent DNA damage, irreversible cell cycle arrest, cell hypertrophy, lipofuscin accumulation, enhanced β-galactosidase activity. Using flame photometry to estimate K+, Na+ content and Rb+ (K+) fluxes we found that during the senescence development in stress-induced hMESCs, Na+/K+pump-mediated K+ fluxes are enhanced due to the increased Na+ content in senescent cells, while ouabain-resistant K+ fluxes remain unchanged. Senescence progression is accompanied by a peculiar decrease in the K+ content in cells from 800-900 µmol/g to 500-600 µmol/g. Since cardiac glycosides are offered as selective agents for eliminating senescent cells, we investigated the effect of ouabain on ion homeostasis and viability of hMESCs and found that in both proliferating and senescent hMESCs, ouabain (1 nM-1 µM, 24-48 h) inhibited pump-mediated K+ transport (ID50 5x10-8 M), decreased cell K+/Na+ ratio to 0,1-0,2, however did not induce apoptosis. Comparison of the effect of ouabain on hMESCs with the literature data on the selective cytotoxic effect of cardiac glycosides on senescent or cancer cells suggests the ion pump blockade and intracellular K+ depletion should be synergized with target apoptotic signal to induce the cell death.
