Abstract
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.
Highlights
The role of Cl− channels and transporters in cellular processes attracts much attention at present (Hoffmann et al, 2015; Jentsch, 2016; Pedersen et al, 2016; Jentsch and Pusch, 2018; Currin et al, 2020; Murillo-de-Ozores et al, 2020)
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
Our previous studies showed that a computation based on the simplest model of cell ionic homeostasis including only the pump; Na+, K+, and Cl− channels; and cotransport NC predicts well the realtime dynamics of changes in ion concentrations and cell water content after blocking the pump even if the constant parameters of channels and NC cotransporter found for normal resting cells were used in calculations (Vereninov et al, 2014, 2016)
Summary
The role of Cl− channels and transporters in cellular processes attracts much attention at present (Hoffmann et al, 2015; Jentsch, 2016; Pedersen et al, 2016; Jentsch and Pusch, 2018; Currin et al, 2020; Murillo-de-Ozores et al, 2020). The current studies in this area focus mostly on the regulation of channels and transporters but not an analysis of their interactions in maintaining the entire ionic homeostasis of cell, regulation of the cell water balance, and generation of electrochemical gradients of ions on the cell membrane (Hoffmann and Pedersen, 2011; Cruz-Rangel et al, 2012; Kaila et al, 2014; Zhang et al, 2016; Shekarabi et al, 2017; de Los Heros et al, 2018; Wilson and Mongin, 2018; Dmitriev et al, 2019; Okada et al, 2019; Song et al, 2019; Bortner and Cidlowski, 2020; Kittl et al, 2020; Murillo-de-Ozores et al, 2020; PachecoAlvarez et al, 2020) We believe that this is partly due to the lack of a suitable computational modeling tool for a rather complex system. The modeling helps to quantify the effects caused by alteration of each ion pathway separately and in combination more rigorously than using specific inhibitors or mutation analysis
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