Red cell volume regulation: the pivotal role of ionic strength in controlling swelling-dependent transport systems

Motais, R; Guizouarn, Hélène; Garcia-Romeu, F

doi:10.1016/0304-4165(91)90248-f

Cited by 99 publications

(64 citation statements)

References 17 publications

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“…Several authors have proposed a mechanism whereby changes in cell volume are detected by a putative ''volume sensor,'' which directly or indirectly regulates the opening of VRAC. A change in ⌫ i was supposed to alter the properties of this ''volume sensor,'' such that, at lower ⌫ i , smaller increases in cell volume are sufficient to activate I Cl,swell (5)(6)(7)18). On the basis of our present results, we argue against such a mechanism in endothelial cells.…”

Section: Discussionmentioning

confidence: 53%

Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume-regulated anion channels

Voets

Droogmans

Raskin

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

129

107

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Most mammalian cell types, including endothelial cells, respond to cell swelling by activating a Cl ؊ current termed I Cl,swell , but it is not known how the physical stimulus of cell swelling is transferred to the channels underlying I Cl,swell . We have investigated the precise relation between cell volume and I Cl,swell in endothelial cells by performing whole-cell current recordings while continuously monitoring cell thickness (T c ) as a measure for cell volume. The time course of T c was accurately predicted by a theoretical model that describes volume changes of patch-clamped cells in response to changes in the extracellular osmolality (OSM o ). This model also predicts significant changes in intracellular ionic strength (⌫ i ) when OSM o is altered. Under all experimental conditions I Cl,swell closely followed the changes in ⌫ i , whereas I Cl,swell and cell volume were often found to change independently. These results do not support the hypothesis that ⌫ i regulates the volume set point for activation of I Cl,swell . Instead, they are in complete agreement with a model in which a decrease of ⌫ i rather than an increase in cell volume is the initial trigger for activation of I Cl,swell .All living cells are programmed to activate a series of cellular processes to counter the harmful effects of cell swelling. One of the first detectable effects of cell swelling in most vertebrate cells is an increase in the plasma membrane permeability to anions, through the opening of anion channels (1). Although different types of swelling-activated anion currents have been functionally described, one phenotype seems to be predominant. This outwardly rectifying current, which under normal conditions is mainly carried by Cl Ϫ , has been termed I Cl,swell for swelling-activated Cl Ϫ current, and the underlying channel has been termed VRAC for volume-regulated anion channel. The biophysical and pharmacological properties of I Cl,swell ͞VRAC have been extensively studied (for recent reviews, see refs. 2-4), but the precise activation mechanism of I Cl,swell is still not resolved. Particularly, it remains unclear how the cell ''senses'' changes in its volume and translates this physical stimulus into the opening of VRAC.Hypotonicity-induced cell swelling is accompanied by a dilution of the intracellular medium, resulting in a decrease of ⌫ i , the intracellular ionic strength. Interestingly, it was recently shown that ⌫ i modulates I Cl,swell , independent of the molecular nature of the intracellular ions. A model was proposed in which ⌫ i regulates the volume set point for activation of VRAC, by modulating a putative ''volume sensor '' (5-7).In the present study we tested this model by investigating the relation between cell volume, ⌫ i , and I Cl,swell in endothelial cells. To this end, we set up a combined system that enables the simultaneous measurement of whole-cell currents and cell thickness (T c ). A theoretical model was developed that accurately predicts the osmotically induced volume changes and the conco...

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Section: Discussionmentioning

confidence: 53%

Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume-regulated anion channels

Voets

Droogmans

Raskin

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

129

107

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“…K+ loss is not, or only slightly, reduced by replacement of Cl-by NO3- (Garcia-Romeu, Cossins & Motais, 1991). Thus in trout erythrocytes two types of volume-dependent K+ pathways co-exist, and we have demonstrated that the cells adopt one rather than the other depending on changes of cellular ionic strength induced by swelling (Motais, Guizouarn & Garcia-Romeu, 1991). An evaluation of the nature of these flux pathways (i.e.…”

Section: Introductionmentioning

confidence: 78%

Volume‐activated Cl(‐)‐independent and Cl(‐)‐dependent K+ pathways in trout red blood cells.

Guizouarn

Harvey

Borgèse

et al. 1993

The Journal of Physiology

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SUMMARY1. Swelling of trout erythrocytes can be induced either by addition of catecholamine to the cell suspension, thus promoting NaCl uptake via fiadrenergic-stimulated Na+-H+ exchange (isotonic swelling) or by suspending red blood cells in a hypotonic medium (hypotonic swelling). In both cases cells tend to regulate their volume by losing K+, but the characteristics of the volume-activated K+ pathways are different: after hormonally induced swelling the K+ loss is strictly Cl-dependent; after hypotonic swelling the K+ loss is essentially Cl-independent.2. In order to determine the nature of these volume regulatory pathways (i.e. whether the net K+ loss was conductive or was by electroneutral K+-H+ exchange or KCl co-transport), studies were performed to analyse ion fluxes and associated electrical phenomena. The cell membrane potential and intracellular ionic activities of volume-regulating and volume-static cells were measured by impalement with conventional microelectrodes and double-barrelled ion-sensitive microelectrodes.3. The information gained from the electrical and ion flux studies leads to the conclusion that both Cl--independent and Cl--dependent K+ loss proceed via electrically silent pathways.4. Experiments were designed to distinguish between electroneutral K+-H+ exchange or KCI co-transport. These were based upon the inhibition of Cl--OHexchange to evaluate the degree of coupling between K+ and Cl-(KCI stoichiometry, pH change). The experimental observations are consistent with the fact that both Cl--independent and Cl--dependent K+ loss are mediated by coupled K+-anion co-transport and not by K+-H+ exchange.5. On the basis of previous data, we suggest that only one type of K+-anion cotransport exists in the cell membrane, for which the selectivity for anions varies according to the change in cellular ionic strength induced by swelling.

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“…To achieve this goal, we manipulated intracellular ionic strength using a variety of methods under different ambient tonicity conditions and investigated subsequent changes in the activity of TonEBP. Concentrations of Na ϩ , K ϩ , and Cl Ϫ were measured by using electron microprobe analysis (2), and their sum was taken as a measure of intracellular ionic strength (16). TonEBP activity on transcription was measured by Northern analyses of the TonEBP target genes AR, BGT1, HSP70, and SMIT.…”

Section: Resultsmentioning

confidence: 99%

Regulation of TonEBP transcriptional activator in MDCK cells following changes in ambient tonicity

Neuhofer

Woo

et al. 2002

American Journal of Physiology-Cell Physiology

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In response to ambient hypertonicity, TonEBP (tonicity-responsive enhancer binding protein) stimulates certain genes including those encoding cytokines, transporters for organic solutes, and a molecular chaperone. TonEBP is regulated in a bidirectional manner, upregulated by an increase in ambient tonicity while downregulated by a decrease. To investigate the role of intracellular ionic strength in the activity of TonEBP, we subjected Madin-Darby canine kidney cells to a variety of conditions. Electron microprobe analysis was performed to measure intracellular electrolytes. Under conditions in which changes in cell volume were similar, TonEBP activity correlated with the intracellular ionic strength regardless of the external tonicity. On the other hand, inhibition of the Na+/K+-ATPase and high external K+ concentration led to a decreased activity of TonEBP despite a marked increase in the intracellular ionic strength. Because isotonic swelling is known to occur under these conditions, these data suggest that dilution of the cytoplasmic constituents inhibits the activity of TonEBP. We conclude that intracellular ionic strength and water content are major factors that determine the activity of TonEBP.

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Red cell volume regulation: the pivotal role of ionic strength in controlling swelling-dependent transport systems

Cited by 99 publications

References 17 publications

Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume-regulated anion channels

Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume-regulated anion channels

Volume‐activated Cl(‐)‐independent and Cl(‐)‐dependent K+ pathways in trout red blood cells.

Regulation of TonEBP transcriptional activator in MDCK cells following changes in ambient tonicity

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