Physiology and pathophysiology of Na+/H+exchange and Na+-K+-2Cl−cotransport in the heart, brain, and blood

2006 ◽  
Vol 291 (1) ◽  
pp. R1-R25 ◽  
Author(s):  
S. F. Pedersen ◽  
M. E. O'Donnell ◽  
S. E. Anderson ◽  
P. M. Cala
Keyword(s):  
Cell Volume ◽  
Cell Function ◽  
Cell Damage ◽  
Cellular Responses ◽  
Exercise Stress ◽  
Cell Swelling ◽  
Cell Shrinkage ◽  
Comprehensive Overview ◽  
Wide Range ◽  
Stimulation Of

Maintenance of a stable cell volume and intracellular pH is critical for normal cell function. Arguably, two of the most important ion transporters involved in these processes are the Na+/H+exchanger isoform 1 (NHE1) and Na+-K+-2Cl−cotransporter isoform 1 (NKCC1). Both NHE1 and NKCC1 are stimulated by cell shrinkage and by numerous other stimuli, including a wide range of hormones and growth factors, and for NHE1, intracellular acidification. Both transporters can be important regulators of cell volume, yet their activity also, directly or indirectly, affects the intracellular concentrations of Na+, Ca2+, Cl−, K+, and H+. Conversely, when either transporter responds to a stimulus other than cell shrinkage and when the driving force is directed to promote Na+entry, one consequence may be cell swelling. Thus stimulation of NHE1 and/or NKCC1 by a deviation from homeostasis of a given parameter may regulate that parameter at the expense of compromising others, a coupling that may contribute to irreversible cell damage in a number of pathophysiological conditions. This review addresses the roles of NHE1 and NKCC1 in the cellular responses to physiological and pathophysiological stress. The aim is to provide a comprehensive overview of the mechanisms and consequences of stress-induced stimulation of these transporters with focus on the heart, brain, and blood. The physiological stressors reviewed are metabolic/exercise stress, osmotic stress, and mechanical stress, conditions in which NHE1 and NKCC1 play important physiological roles. With respect to pathophysiology, the focus is on ischemia and severe hypoxia where the roles of NHE1 and NKCC1 have been widely studied yet remain controversial and incompletely elucidated.

Regulation of cell function by the cellular hydration state

1994 ◽  
Vol 267 (3) ◽  
pp. E343-E355 ◽  
Author(s):  
D. Haussinger ◽  
F. Lang ◽  
W. Gerok
Keyword(s):  
Cell Volume ◽  
Cell Function ◽  
Narrow Range ◽  
Cell Swelling ◽  
Metabolic Function ◽  
Cell Shrinkage ◽  
Short Term ◽  
Hydration State ◽  
Per Se ◽  
And Oxidative Stress

Cellular hydration can change within minutes under the influence of hormones, nutrients, and oxidative stress. Such short-term modulation of cell volume within a narrow range acts per se as a potent signal which modifies cellular metabolism and gene expression. It appears that cell swelling and cell shrinkage lead to certain opposite patterns of cellular metabolic function. Apparently, hormones and amino acids can trigger those patterns simply by altering cell volume. Thus alterations of cellular hydration may represent another important mechanism for metabolic control and act as another second or third messenger linking cell function to hormonal and environmental alterations.

scholarly journals Cell volume and bile acid excretion

1992 ◽  
Vol 288 (2) ◽  
pp. 681-689 ◽  
Author(s):  
D Häussinger ◽  
C Hallbrucker ◽  
N Saha ◽  
F Lang ◽  
W Gerok
Keyword(s):  
Amino Acids ◽  
Cell Volume ◽  
Liver Cell ◽  
Bile Flow ◽  
Cell Swelling ◽  
Isolated Perfused Rat Liver ◽  
Cell Shrinkage ◽  
Volume Changes ◽  
Close Relationship ◽  
Stimulation Of

The interaction between cell volume and taurocholate excretion into bile was studied in isolated perfused rat liver. Cell swelling due to hypo-osmotic exposure, addition of amino acids or insulin stimulated taurocholate excretion into bile and bile flow, whereas hyperosmotic cell shrinkage inhibited these. These effects were explained by changes in Vmax of taurocholate excretion into bile: Vmax. increased from about 300 to 700 nmol/min per g after cell swelling by 12-15% caused by either hypo-osmotic exposure or addition of amino acids under normo-osmotic conditions. Steady-state taurocholate excretion into bile was not affected when the influent K+ concentration was increased from 6 to 46 mM or decreased to 1 mM with iso-osmoticity being maintained by corresponding changes in the influent Na+ concentration. Replacement of 40 mM-NaCl by 80 mM-sucrose decreased taurocholate excretion into bile by about 70%; subsequent hypo-osmotic exposure by omission of sucrose increased taurocholate excretion to 160%. Only minor, statistically insignificant, effects of aniso-osmotic cell volume changes on the appearance of bolus-injected horseradish peroxidase in bile were observed. Taurocholate (400 microM) exhibited a cholestatic effect during hyperosmotic cell shrinkage, but not during hypo-osmotic cell swelling. Both taurocholate and tauroursodeoxycholate increased liver cell volume. Tauroursodeoxycholate stimulated taurocholate (100 microM) excretion into bile. This stimulatory effect was strongly dependent on the extent of tauroursodeoxycholate-induced cell swelling. During continuous infusion of taurocholate (100 microM) further addition of tauroursodeoxycholate at concentrations of 20, 50 and 100 microM increased cell volume by 10, 8 and 2% respectively, in parallel with a stimulation of taurocholate excretion into bile by 29, 27 and 9% respectively. There was a close relationship between the extent of cell volume changes and taurocholate excretion into bile, regardless of whether cell volume was modified by tauroursodeoxycholate, amino acids or aniso-osmotic exposure. The data suggest that: (i) liver cell volume is one important factor determining bile flow and biliary taurocholate excretion; (ii) swelling-induced stimulation of taurocholate excretion into bile is probably not explained by alterations of the membrane potential; (iii) bile acids modulate liver cell volume; (iv) taurocholate-induced cholestasis may depend on cell volume; (v) stimulation of taurocholate excretion into bile by tauroursodeoxycholate can largely be explained by tauroursodeoxycholate-induced cell swelling.

Volume-sensitive Ca influx and release from intracellular pools in gastric parietal cells

1992 ◽  
Vol 263 (3) ◽  
pp. C584-C589 ◽  
Author(s):  
P. A. Negulescu ◽  
B. Munck ◽  
T. E. Machen
Keyword(s):  
Image Processing ◽  
Cell Volume ◽  
Digital Image Processing ◽  
Parietal Cells ◽  
Cell Swelling ◽  
Cell Shrinkage ◽  
Gastric Glands ◽  
Intact Rabbit ◽  
Induced Changes ◽  
Gastric Parietal Cells

The effects of osmotically induced changes in cell volume on cytoplasmic free Ca (Cai) were studied in parietal cells from intact rabbit gastric glands using digital image processing of fura-2 fluorescence. In resting unstimulated cells, Cai was unaffected by either cell swelling or shrinking when osmolarity was varied between 200 and 400 mosM (isotonicity 290 mosM). However, when cells were swelled in a 165 mosM solution (55% tonicity), a biphasic Ca increased was observed. On average, Cai increased transiently from 80 to 218 nM before stabilizing at approximately 140 nM. The peak was due to release from intracellular pools because it was present in Ca-free solutions while the sustained elevation was dependent on external Ca. In carbachol-stimulated cells, Ca influx was most sensitive to cell shrinkage. For example, addition of 25 mM sucrose (108% tonicity) caused a 30% decrease in the sustained carbachol-stimulated Cai increase (plateau). In contrast, carbachol-stimulated cells were relatively insensitive to cell swelling, with a 30% decrease in tonicity causing only a 15% increase in the plateau. However, as in the unstimulated cells, extreme (55% tonicity) swelling caused additional increases in Cai levels. The carbachol-dependent effects of changes in cell volume on Cai could be mimicked by treating cells with thapsigargin, an inhibitor of Ca pumps of intracellular membranes that also has been shown to stimulate Ca entry. Thus, although extreme swelling conditions (55% tonicity) could elicit Cai increases in either the presence or absence of agonist, agonist was required to observe Cai decreases due to cell shrinkage.(ABSTRACT TRUNCATED AT 250 WORDS)

Agonist-induced cytoplasmic volume changes in cultured rabbit parietal cells

2000 ◽  
Vol 279 (1) ◽  
pp. G40-G48 ◽  
Author(s):  
Thorsten Sonnentag ◽  
Wolf-Kristian Siegel ◽  
Oliver Bachmann ◽  
Heidi Rossmann ◽  
Andreas Mack ◽  
...  
Keyword(s):  
Volume Regulation ◽  
Parietal Cells ◽  
Cell Swelling ◽  
Secretory Process ◽  
Cell Shrinkage ◽  
Rapid Loss ◽  
Volume Changes ◽  
Volume Increase ◽  
Regulatory Volume Increase ◽  
Stimulation Of

Concomitant Na+/H+ and Cl−/HCO3 − exchange activation occurs during stimulation of acid secretion in cultured rabbit parietal cells, possibly related to a necessity for volume regulation during the secretory process. We investigated whether cytoplasmic volume changes occur during secretagogue stimulation of cultured rabbit parietal cells. Cells were loaded with the fluorescent dye calcein, and the calcein concentration within a defined cytoplasmic volume was recorded by confocal microscopy. Forskolin at 10−5 M, carbachol at 10−4 M, and hyperosmolarity (400 mosmol) resulted in a rapid increase in the cytoplasmic dye concentration by 21 ± 6, 9 ± 4, and 23 ± 5%, respectively, indicative of cell shrinkage, followed by recovery to baseline within several minutes, indicative of regulatory volume increase (RVI). Depolarization by 5 mM barium resulted in a decrease of the cytoplasmic dye concentration by 10 ± 2%, indicative of cell swelling, with recovery within 15 min, and completely prevented forskolin- or carbachol-induced cytoplasmic shrinkage. Na+/H+ exchange inhibitors slightly reduced the initial cell shrinkage and significantly slowed the RVI, whereas 100 μM bumetanide had no significant effect on either parameter. We conclude that acid secretagoguges induce a rapid loss of parietal cell cytoplasmic volume, followed by RVI, which is predominantly mediated by Na+/H+ and Cl−/HCO3 − exchange.

New activity of yamamarin, an insect pentapeptide, on immune system of mealworm,Tenebrio molitor

2017 ◽  
Vol 108 (3) ◽  
pp. 351-359 ◽  
Author(s):  
K. Walkowiak-Nowicka ◽  
G. Nowicki ◽  
M. Kuczer ◽  
G. Rosiński
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Cellular Responses ◽  
Tenebrio Molitor ◽  
Immunotropic Activity ◽  
Silk Moth ◽  
Wide Range ◽  
Selected Functions ◽  
Active Substances ◽  
Stimulation Of

AbstractIn insects, two types of the immune responses, cellular and humoral, constitute a defensive barrier against various parasites and pathogens. In response to pathogens, insects produce a wide range of immune agents that act on pathogens directly, such as cecropins or lysozyme, or indirectly by the stimulation of hemocyte migration or by increasing phenoloxidase (PO) activity. Recently, many new immunologically active substances from insects, such as peptides and polypeptides, have been identified. Nevertheless, in the most cases, their physiological functions are not fully known. One such substance is yamamarin – a pentapeptide isolated from the silk mothAntheraea yamamai. This yamamarin possesses strong antiproliferative properties and is probably involved in diapause regulation. Here, we examined the immunotropic activity of yamamarin by testing its impact on selected functions of the immune system in heterologous bioassays with the beetleTenebrio molitor, commonly known as a stored grains pest. Our results indicate that the pentapeptide affects the activity of immune processes in the beetle. We show that yamamarin induces changes in both humoral and cellular responses. The yamamarin increases the activity of PO, as well as causes changes in the hemocyte cytoskeleton and stimulates phagocytic activity. We detected an increased number of apoptotic hemocytes, however after the yamamarin injection, no significant variations in the antibacterial activity in the hemolymph were observed. The obtained data suggest that yamamarin could be an important controller of the immune system inT. molitor.

Effects of apical membrane Cl(-)-formate exchange on cell volume in rabbit proximal tubule

1990 ◽  
Vol 258 (3) ◽  
pp. F530-F536 ◽  
Author(s):  
L. Schild ◽  
P. S. Aronson ◽  
G. Giebisch
Keyword(s):  
Proximal Tubule ◽  
Cell Volume ◽  
Apical Membrane ◽  
Cell Swelling ◽  
Volume Changes ◽  
Proximal Tubule Cells ◽  
Volume Increase ◽  
Tubule Lumen ◽  
Stimulation Of

We used real-time recordings of cell volume changes to test for the role of the Cl(-)-formate exchanger in mediating NaCl entry across the apical membrane of rabbit proximal tubule cells. In the absence of extracellular Cl-, 0.5 and 5 mM formate in the tubule lumen induced an increase in cell volume of 1 and 9%, respectively. Formate-induced cell swelling was reduced by alkalinizing the tubule lumen or by addition of luminal amiloride (2 mM), indicating that the increase in cell volume results from the intracellular accumulation of Na-formate via nonionic diffusion of formic acid in parallel with Na(+)-H+ exchange. The cell volume increase induced by 0.5 mM formate was potentiated (from 1 to 4%) by Cl-, as expected for a formate-mediated stimulation of NaCl uptake via parallel Cl(-)-formate exchange and Na(+)-H+ exchange across the apical membrane. By contrast, the cell volume increase induced by 5 mM formate was attenuated (from 9 to 4%) by Cl-. The attenuating effect of Cl- on formate-induced cell swelling required the operation of the apical membrane Cl(-)-formate exchanger. The effect of 1:1 Cl(-)-formate exchange to attenuate formate-induced cell swelling can be explained if the cell possesses a volume-activated anion exit pathway, most likely at the basolateral cell membrane, that is capable of mediating the efflux of Cl- but not formate from the cell.

scholarly journals The role of cell swelling in the stimulation of glycogen synthesis by insulin

1992 ◽  
Vol 282 (3) ◽  
pp. 789-796 ◽  
Author(s):  
M al-Habori ◽  
M Peak ◽  
T H Thomas ◽  
L Agius
Keyword(s):  
Cell Volume ◽  
Glycogen Synthesis ◽  
Metabolic Effects ◽  
Cell Swelling ◽  
Free Medium ◽  
K Uptake ◽  
Osmotic Swelling ◽  
Cation Content ◽  
Secondary Mechanism ◽  
Stimulation Of

In hepatocyte cultures, insulin stimulates cellular accumulation of K+, partly (approximately 20%) by net replacement of cell Na+, but largely (approximately 80%) by increasing the cell K++Na+ content, with a consequent increase in cell volume. An increase in cation content occurred within 5 min of exposure to insulin and was not secondary to metabolic changes. Insulin also increased the cation content, by increasing the Na+ content, in a K(+)-free medium or when K+ uptake was inhibited with 1 mM-ouabain. However, insulin did not increase the cation content in a Na(+)-free medium. The stimulation of glycogen synthesis by insulin, like the increase in cation content, was blocked in a Na(+)-free medium, but not when K+ uptake was inhibited. Hypo-osmotic swelling restored the stimulation of glycogen synthesis in a Na(+)-free medium, indicating that the lack of effect of insulin in the iso-osmotic Na(+)-free medium was not due to a direct requirement for Na+ for glycogen synthesis, but to a secondary mechanism, dependent on Na+ entry, that can be mimicked by hypo-osmotic swelling. Quinine increased cell volume further and caused a further increase in glycogen synthesis. The hypothesis that cellular uptake of K+ may be part of the mechanism by which insulin controls metabolism was discounted, because inhibition of K+ uptake does not block the metabolic effects of insulin [Czech (1977) Annu. Rev. Biochem. 46, 359-384]. The present results support the hypothesis that an increase in cell cation content, and thereby cell volume, rather than K+ uptake, is part of the mechanism by which insulin stimulates glycogen synthesis in hepatocytes.

Effects of osmotic stress on the activity of MAPKs and PDGFR-β-mediated signal transduction in NIH-3T3 fibroblasts

2008 ◽  
Vol 294 (4) ◽  
pp. C1046-C1055 ◽  
Author(s):  
M.-B. Nielsen ◽  
S. T. Christensen ◽  
E. K. Hoffmann
Keyword(s):  
Signal Transduction ◽  
Osmotic Stress ◽  
Cell Volume ◽  
Nuclear Translocation ◽  
Cell Swelling ◽  
Cell Shrinkage ◽  
Jnk Pathway ◽  
Mapk Activity ◽  
3T3 Fibroblasts ◽  
Nih 3T3

Signaling in cell proliferation, cell migration, and apoptosis is highly affected by osmotic stress and changes in cell volume, although the mechanisms underlying the significance of cell volume as a signal in cell growth and death are poorly understood. In this study, we used NIH-3T3 fibroblasts in a serum- and nutrient-free inorganic medium (300 mosM) to analyze the effects of osmotic stress on MAPK activity and PDGF receptor (PDGFR)-β-mediated signal transduction. We found that hypoosmolarity (cell swelling at 211 mosM) induced the phosphorylation and nuclear translocation of ERK1/2, most likely via a pathway independent of PDGFR-β and MEK1/2. Conversely, hyperosmolarity (cell shrinkage at 582 mosM) moved nuclear and phosphorylated ERK1/2 to the cytoplasm and induced the phosphorylation and nuclear translocation of p38 and phosphorylation of JNK1/2. In a series of parallel experiments, hypoosmolarity did not affect PDGF-BB-induced activation of PDGFR-β, whereas hyperosmolarity strongly inhibited ligand-dependent PDGFR-β activation as well as downstream mitogenic signal components of the receptor, including Akt and the MEK1/2-ERK1/2 pathway. Based on these results, we conclude that ligand-dependent activation of PDGFR-β and its downstream effectors Akt, MEK1/2, and ERK1/2 is strongly modulated (inhibited) by hyperosmotic cell shrinkage, whereas cell swelling does not seem to affect the activation of the receptor but rather to activate ERK1/2 via a different mechanism. It is thus likely that cell swelling via activation of ERK1/2 and cell shrinkage via activation of the p38 and JNK pathway and inhibition of the PDGFR signaling pathway may act as key players in the regulation of tissue homeostasis.

scholarly journals WNK3 and WNK4 exhibit opposite sensitivity with respect to cell volume and intracellular chloride concentration

2020 ◽  
Vol 319 (2) ◽  
pp. C371-C380
Author(s):  
Diana Pacheco-Alvarez ◽  
Diego Luis Carrillo-Pérez ◽  
Adriana Mercado ◽  
Karla Leyva-Ríos ◽  
Erika Moreno ◽  
...  
Keyword(s):  
Cell Volume ◽  
Chloride Concentration ◽  
Cell Swelling ◽  
Cell Shrinkage ◽  
Serine Threonine Kinase ◽  
Intracellular Chloride ◽  
Highly Sensitive ◽  
A Cell ◽  
Carboxy Terminal ◽  
Intracellular Chloride Concentration

Cation-coupled chloride cotransporters (CCC) play a role in modulating intracellular chloride concentration ([Cl−]i) and cell volume. Cell shrinkage and cell swelling are accompanied by an increase or decrease in [Cl−]i, respectively. Cell shrinkage and a decrease in [Cl−]i increase the activity of NKCCs (Na-K-Cl cotransporters: NKCC1, NKCC2, and Na-Cl) and inhibit the activity of KCCs (K-Cl cotransporters: KCC1 to KCC4), wheras cell swelling and an increase in [Cl−]i activate KCCs and inhibit NKCCs; thus, it is unlikely that the same kinase is responsible for both effects. WNK1 and WNK4 are chloride-sensitive kinases that modulate the activity of CCC in response to changes in [Cl−]i. Here, we showed that WNK3, another member of the serine-threonine kinase WNK family with known effects on CCC, is not sensitive to [Cl−]i but can be regulated by changes in extracellular tonicity. In contrast, WNK4 is highly sensitive to [Cl−]i but is not regulated by changes in cell volume. The activity of WNK3 toward NaCl cotransporter is not affected by eliminating the chloride-binding site of WNK3, further confirming that the kinase is not sensitive to chloride. Chimeric WNK3/WNK4 proteins were produced, and analysis of the chimeras suggests that sequences within the WNK’s carboxy-terminal end may modulate the chloride affinity. We propose that WNK3 is a cell volume-sensitive kinase that translates changes in cell volume into phosphorylation of CCC.

scholarly journals Coordinate modulation of Na-K-2Cl cotransport and K-Cl cotransport by cell volume and chloride

2002 ◽  
Vol 283 (5) ◽  
pp. C1422-C1431 ◽  
Author(s):  
Christian Lytle ◽  
Thomas McManus
Keyword(s):  
Cell Volume ◽  
Cell Volume Regulation ◽  
Specific Effect ◽  
Feedback System ◽  
Major Effect ◽  
Cell Swelling ◽  
Cell Shrinkage ◽  
Set Point

Na-K-2Cl cotransporter (NKCC) and K-Cl cotransporter (KCC) play key roles in cell volume regulation and epithelial Cl− transport. Reductions in either cell volume or cytosolic Cl− concentration ([Cl−]i) stimulate a corrective uptake of KCl and water via NKCC, whereas cell swelling triggers KCl loss via KCC. The dependence of these transporters on volume and [Cl−]i was evaluated in model duck red blood cells. Replacement of [Cl−]i with methanesulfonate elevated the volume set point at which NKCC activates and KCC inactivates. The set point was insensitive to cytosolic ionic strength. Reducing [Cl−]i at a constant driving force for inward NKCC and outward KCC caused the cells to adopt the new set point volume. Phosphopeptide maps of NKCC indicated that activation by cell shrinkage or low [Cl−]iis associated with phosphorylation of a similar constellation of Ser/Thr sites. Like shrinkage, reduction of [Cl−]i accelerated NKCC phosphorylation after abrupt inhibition of the deactivating phosphatase with calyculin A in vivo, whereas [Cl−] had no specific effect on dephosphorylation in vitro. Our results indicate that NKCC and KCC are reciprocally regulated by a negative feedback system dually modulated by cell volume and [Cl−]. The major effect of Cl− on NKCC is exerted through the volume-sensitive kinase that phosphorylates the transport protein.

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