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1.
Cell swelling, regulatory volume decrease (RVD), volume-sensitive Cl (Cl swell) current and taurine efflux after exposure to high concentrations of urea were characterized in fibroblasts Swiss 3T3, and results compared to those elicited by hyposmotic (30%) swelling. Urea 70, 100, and 150 mM linearly increased cell volume (8.25%, 10.6%, and 15.7%), by a phloretin-inhibitable process. This was followed by RVD by which cells exposed to 70, 100, or 150 mM urea recovered 27.6%, 38.95, and 74.1% of their original volume, respectively. Hyposmolarity (30%) led to a volume increase of 25.9% and recovered volume in 32.5%. 3H-taurine efflux was increased by urea with a sigmoid pattern, as 9.5%, 18.9%, 71.5%, and 89% of the labeled taurine pool was released by 70, 100, 150, or 200 mM urea, respectively. Only about 11% of taurine was released by 30% hyposmolarity reduction in spite of the high increase in cell volume. Urea-induced taurine efflux was suppressed by NPPB (100 μM) and markedly reduced by the tyrosine kinase-general blocker AG18. The Cl swell current was more rapidly activated and higher in amplitude in the hyposmotic than in the isosmotic/urea condition (urea 150 mM), but this was not sufficient to accomplish an efficient RVD. These results showed that at similar volume increase, cells swollen by urea showed higher taurine efflux, lower Cl swell current and more efficient RVD, than in those swollen by hyposmolarity. The correlation found between RVD efficiency and taurine efflux suggest a prominent role for organic over ionic osmolytes for RVD evoked by urea in isosmotic conditions.  相似文献   

2.
Ilyaskin  A. V.  Baturina  G. S.  Medvedev  D. A.  Ershov  A. P.  Solenov  E. I. 《Biophysics》2011,56(3):516-524
The reaction of rat kidney collecting duct principal cells to hypotonic shock was studied. The changes in cell relative volume were measured using fluorescent dye calcein, and a mathematical model based on our experimental results was developed. It was shown that regulatory volume decrease is mainly provided by significant release of osmolytes from the cell and decrease of the plasma membrane water permeability. Using our model, we calculated the membrane water permeability and found it to decrease from 2 · 10−1 to 2 · 10−2 cm/s. We conclude that for effective RVD to occur, a dramatic increase in the membrane permeability to K+, Cl and organic anions is necessary.  相似文献   

3.
An in-depth understanding of the mechanisms underlying regulatory volume behavior in corneal epithelial cells has been in part hampered by the lack of adequate methodology for characterizing this phenomenon. Accordingly, we developed a novel approach to characterize time-dependent changes in relative cell volume induced by anisosmotic challenges in calcein-loaded SV40-immortalized human corneal epithelial (HCE) cells with a fluorescence microplate analyzer. During a hypertonic challenge, cells shrank rapidly, followed by a temperature-dependent regulatory volume increase (RVI), τc = 19 min. In contrast, a hypotonic challenge induced a rapid (τc = 2.5 min) regulatory volume decrease (RVD). Temperature decline from 37 to 24°C reduced RVI by 59%, but did not affect RVD. Bumetanide (50 μM), ouabain (1 mM), DIDS (1 mM), EIPA (100 μM), or Na+-free solution reduced the RVI by 60, 61, 39, 32, and 69%, respectively. K+, Cl channel and K+-Cl cotransporter (KCC) inhibition obtained with either 4-AP (1 mM), DIDS (1 mM), DIOA (100 μM), high K+ (20 mM) or Cl-free solution, suppressed RVD by 42, 47, 34, 52 and 58%, respectively. KCC activity also affects steady-state cell volume, since its inhibition or stimulation induced relative volume alterations under isotonic conditions. Taken together, K+ and Cl channels in parallel with KCC activity are important mediators of RVD, whereas RVI is temperature-dependent and is essentially mediated by the Na+-K+-2Cl cotransporter (Na+-K+-2Cl) and the Na+-K+ pump. Inhibition of K+ and Cl channels and KCC but not Na+-K+-2Cl affect steady-state cell volume under isotonic conditions. This is the first report that KCC activity is required for HCE cell volume regulation and maintenance of steady-state cell volume.  相似文献   

4.
This study describes the correlation between cell swelling-induced K+ efflux and volume regulation efficiency evaluated with agents known to modulate ion channel activity and/or intracellular signaling processes in a human bronchial epithelial cell line, 16HBE14o−1. Cells on permeable filter supports, differentiated into polarized monolayers, were monitored continuously at room temperature for changes in cell height (Tc), as an index of cell volume, whereas 86Rb efflux was assessed for K+ channel activity. The sudden reduction in osmolality of both the apical and basolateral perfusates (from 290 to 170 mosmol/kg H2O) evoked a rapid increase in cell volume by 35%. Subsequently, the regulatory volume decrease (RVD) restored cell volume almost completely (to 94% of the isosmotic value). The basolateral 86Rb efflux markedly increased during the hyposmotic shock, from 0.50 ± 0.03 min−1 to a peak value of 6.32 ± 0.07 min−1, while apical 86Rb efflux was negligible. Channel blockers, such as GdCl3 (0.5 mM), quinine (0.5 mM) and 5-nitro-2-(3-phenyl-propylamino) benzoic acid (NPPB, 100 μM), abolished the RVD. The protein tyrosine kinase inhibitors tyrphostin 23 (100 μM) and genistein (150 μM) attenuated the RVD. All agents decreased variably the hyposmosis-induced elevation in 86Rb efflux, whereas NPPB induced a complete block, suggesting a link between basolateral K+ and Cl−1 efflux. Forskolin-mediated activation of adenylyl cyclase stimulated the RVD with a concomitant increase in basolateral 86Rb efflux. These data suggest that the basolateral extrusion of K+ and Cl−1 from 16HBE14o−1 cells in response to cell swelling determines RVD efficiency.  相似文献   

5.
The response of isolated digestive cells of the digestive gland of Mytilus galloprovincialis to hypotonic shock was studied using videometric methods. The isolated cells exposed to a rapid change (from 1100 to 800 mosmol kg?1) of the bathing solution osmolality swelled but thereafter underwent a regulatory volume decrease (RVD), tending to recover the original size. When the hypotonic stress was applied in the presence of quinine and glibenclamide, known inhibitors of swelling activated ion channels, the cells did not exhibit an RVD response; in addition, they showed a larger increase in size in respect to control cells. These observations suggest that the digestive cells of the digestive gland have the machinery to cope with the hyposmotic shock allowing them to exhibit a small but significant RVD preventing an excessive increase in cell size. The pharmacological treatment of digestive cells during the RVD experiments suggests that cell volume is regulated by K+ and Cl? efflux followed by an obliged water efflux from the cell. The involvement of organic osmolytes such as taurine and betaine seems to be excluded by NMR measurement on digestive cells. Copyright © 2012 John Wiley & Sons, Ltd.  相似文献   

6.
Regulatory volume decrease (RVD) following hyposmotic stimulation was studied in isolated turbot, Scophthalmus maximus, hepatocytes. Exposed to a reduced osmolality (from 320 to 240 mosm kg−1), cells first swelled and then exhibited a RVD. Volume regulation was significantly inhibited in presence of NPPB, 9-AC, acetazolamide, DIDS and barium. Taken together, these results could suggest that RVD operated via separate K+ and Cl- channels and probably Cl-/HCO 3 exchanger in turbot hepatocytes. The K+/Cl- cotransporter could also be involved as furosemide and DIOA strongly inhibited the process whereas NEM, a K+/Cl- cotransporter activator, added under isosmotic conditions, led to cell shrinkage. RVD in turbot hepatocytes appeared also to depend on proteins p38 MAP kinase and tyrosine kinase but not on proteins ERK 1/2. Arachidonic acid and leukotrienes could also be involved since inhibition of synthesis of both these compounds by quinacrine and NDGA, respectively, inhibited the volume regulation. Likewise, Ca2+ has been proved to be an essential messenger as RVD was prevented in absence of Ca2+. Finally, this work provides bases for novel studies on cell volume regulation in marine teleosteans.  相似文献   

7.
There is evidence that depolarization of the pancreatic β cell by glucose involves cell swelling and activation of the volume-regulated anion channel (VRAC). However, it is unclear whether cell swelling per se or accompanying changes in intracellular osmolality and/or ionic strength are responsible for VRAC activation. VRAC activity was measured in rat β cells by conventional or perforated patch whole-cell recording. Cell volume was measured by video imaging. In conventional whole-cell recordings, VRAC activation was achieved by exposure of the cells to a hyposmotic bath solution, by application of positive pressure to the pipette, or by use of a hyperosmotic pipette solution. Increased concentrations of intracellular CsCl also caused channel activation, but with delayed kinetics. In perforated patch recordings, VRAC activation was induced by isosmotic addition of the permeable osmolytes urea, 3-Ο-methyl glucose, arginine, and NH4Cl. These effects were all accompanied by β-cell swelling. It is concluded that increased cell volume, whether accompanied by raised intracellular osmolality or ionic strength, is a major determinant of VRAC activation in the β cell. However, increased intracellular ionic strength markedly reduced the rate of VRAC activation. These findings are consistent with the hypothesis that the accumulation of glucose metabolites in the β cell, and the resultant increase in cell volume, provides a signal coupling glucose metabolism with VRAC activation.  相似文献   

8.
The majority of mammalian cells demonstrate regulatory volume decrease (RVD) following swelling caused by hyposmotic exposure. A critical signal initiating RVD is activation of nucleotide receptors by ATP. Elevated extracellular ATP in response to cytotoxic cell swelling during pathological conditions also may initiate loss of taurine and other intracellular osmolytes via anion channels. This study characterizes neuronal ATP-activated anion current and explores its role in net loss of amino acid osmolytes. To isolate anion currents, we used CsCl as the major electrolyte in patch electrode and bath solutions and blocked residual cation currents with NiCl(2) and tetraethylammonium. Anion currents were activated by extracellular ATP with a K(m) of 70 microM and increased over fourfold during several minutes of ATP exposure, reaching a maximum after 9.0 min (SD 4.2). The currents were blocked by inhibitors of nucleotide receptors and volume-regulated anion channels (VRAC). Currents showed outward rectification and inactivation at highly depolarizing membrane potentials, characteristics of swelling-activated anion currents. P2X agonists failed to activate the anion current, and an inhibitor of P2X receptors did not block the effect of ATP. Furthermore, current activation was observed with extracellular ADP and 2-(methylthio)adenosine 5'-diphosphate, a P2Y(1) receptor-specific agonist. Much less current activation was observed with extracellular UTP, suggesting the response is mediated predominantly by P2Y(1) receptors. ATP caused a dose-dependent loss of taurine and alanine that could be blocked by inhibitors of VRAC. ATP did not inhibit the taurine uptake transporter. Thus extracellular ATP triggers a loss of intracellular organic osmolytes via activation of anion channels. This mechanism may facilitate neuronal volume homeostasis during cytotoxic edema.  相似文献   

9.
Cell swelling activates an outwardly rectifying anion current in numerous mammalian cell types. An extensive body of evidence indicates that the channel responsible for this current is the major pathway for volume regulatory organic osmolyte loss. Cell swelling also activates an outwardly rectifying anion current in Xenopus oocytes. Unlike mammalian cells, oocytes allow the direct study of both swelling-activated anion current and organic osmolyte efflux under nearly identical experimental conditions. We therefore exploited the unique properties of oocytes in order to examine further the relationship between anion channel activity and swelling-activated organic osmolyte transport. Swelling-activated anion current and organic osmolyte efflux were studied in parallel in batches of oocytes obtained from single frogs. The magnitude of swelling-activated anion current and organic osmolyte efflux exhibited a positive linear correlation. In addition, the two processes had similar pharmacological characteristics and activation, rundown and reactivation kinetics. The present study provides further strong support for the concept that the channel responsible for swelling-activated Cl efflux and the outwardly rectifying anion conductance is also the major pathway by which organic osmolytes are lost from vertebrate cells during regulatory volume decrease. Received: 22 April 1996/Revised: 18 December 1996  相似文献   

10.
Apoptotic cell death in mammalian models is frequently associated with cell shrinkage. Inhibition of apoptotic volume decrease (AVD) is cytoprotective, suggesting that cell shrinkage is an important early event in apoptosis. In salmonid hepatoma and gill cells staurosporine induced apoptosis, as assessed by activation of effector caspases, nuclear condensation, and a decrease of mitochondrial membrane potential (MMP), and these changes were accompanied by cell shrinkage. The Cl transport inhibitor DIDS and the K+ channel inhibitor quinidine prevented AVD, but only DIDS inhibited apoptosis. Other Cl flux inhibitors, as well as a pan-caspase inhibitor, did not prevent cell shrinkage, but still prevented caspase activation. Furthermore, regulatory volume decrease (RVD) under hypotonic conditions was not facilitated, but diminished in apoptotic cells. Since all transport inhibitors used blocked RVD, but only DIDS and quinidine inhibited AVD, the ion transporters involved in both processes are apparently not identical. In addition, our data indicate that inhibition of Cl fluxes rather than blocking cell shrinkage or K+ fluxes is important for preventing apoptosis. In line with this, inhibition of MAP kinases reduced RVD and not AVD, but still diminished caspase activation. Finally, we observed that MAP kinases were activated upon staurosporine treatment and that at least activation of ERK was prevented when AVD was inhibited.  相似文献   

11.
Change in the intracellular concentration of osmolytes or the extracellular tonicity results in a rapid transmembrane water flow in mammalian cells until intracellular and extracellular tonicities are equilibrated. Most cells respond to the osmotic cell swelling by activation of volume-sensitive flux pathways for ions and organic osmolytes to restore their original cell volume. Taurine is an important organic osmolyte in mammalian cells, and taurine release via a volume-sensitive taurine efflux pathway is increased and the active taurine uptake via the taurine specific taurine transporter TauT decreased following osmotic cell swelling. The cellular signaling cascades, the second messengers profile, the activation of specific transporters, and the subsequent time course for the readjustment of the cellular content of osmolytes and volume vary from cell type to cell type. Using Ehrlich ascites tumor cells, NIH3T3 mouse fibroblasts and HeLa cells as biological systems, it is revealed that phospholipase A2-mediated mobilization of arachidonic acid from phospholipids and subsequent oxidation of the fatty acid via lipoxygenase systems to potent eicosanoids are essential elements in the signaling cascade that is activated by cell swelling and leads to release of osmolytes. The cellular signaling cascade and the activity of the volume-sensitive taurine efflux pathway are modulated by elements of the cytoskeleton, protein tyrosine kinases/phosphatases, GTP-binding proteins, Ca2+/calmodulin, and reactive oxygen species and nucleotides. Serine/threonine phosphorylation of the active taurine uptake system TauT or a putative regulator, as well as change in the membrane potential, are important elements in the regulation of TauT activity. A model describing the cellular sequence, which is activated by cell swelling and leads to activation of the volume-sensitive efflux pathway, is presented at the end of the review.  相似文献   

12.
Regulatory volume decrease (RVD) is a protective mechanism that allows mammalian cells to restore their volume when exposed to a hypotonic environment. A key component of RVD is the release of K+, Cl, and organic osmolytes, such as taurine, which then drives osmotic water efflux. Previous experiments have indicated that caveolin-1, a coat protein of caveolae microdomains in the plasma membrane, promotes the swelling-induced Cl current (ICl,swell) through volume-regulated anion channels. However, it is not known whether the stimulation by caveolin-1 is restricted to the release of Cl or whether it also affects the swelling-induced release of other components, such as organic osmolytes. To address this problem, we have studied ICl,swell and the hypotonicity-induced release of taurine and ATP in wild-type Caco-2 cells that are caveolin-1 deficient and in stably transfected Caco-2 cells that express caveolin-1. Electrophysiological characterization of wild-type and stably transfected Caco-2 showed that caveolin-1 promoted ICl,swell, but not cystic fibrosis transmembrane conductance regulator currents. Furthermore, caveolin-1 expression stimulated the hypotonicity-induced release of taurine and ATP in stably transfected Caco-2 cells grown as a monolayer. Interestingly, the effect of caveolin-1 was polarized because only the release at the basolateral membrane, but not at the apical membrane, was increased. It is therefore concluded that caveolin-1 facilitates the hypotonicity-induced release of Cl, taurine, and ATP, and that in polarized epithelial cells, the effect of caveolin-1 is compartmentalized to the basolateral membrane. caveolae; osmolyte; epithelial cell; chloride channel  相似文献   

13.
The accumulation of inorganic and organic osmolytes and their role in osmotic adjustment were investigated in roots and leaves of vetiver grass (Vetiveria zizanioides) seedlings stressed with 100, 200, and 300 mM NaCl for 9 days. The results showed that, although the contents of inorganic (K+, Na+, Ca2+, Mg2+, Cl, NO3, SO42− and H2PO3)) and organic (soluble sugar, organic acids, and free amino acids) osmolytes all increased with NaCl concentration, the contribution of inorganic ions (mainly Na+, K+, and Cl) to osmotic adjustment was higher (71.50–80.56% of total) than that of organic solutes (19.43–28.50%). The contribution of inorganic ions increased and that of organic solutes decreased in roots with the enhanced NaCl concentration, whereas the case in leaves was opposite. On the other hand, the osmotic adjustment was only effective for vetiver grass seedlings under moderate saline stress (less than 200 mM NaCl).  相似文献   

14.
The K+, Na+, and Cl balance and K+ (Rb+) and 36Cl fluxes in U937 cells induced to apoptosis by 0.2 or 1 μM staurosporine were studied using flame emission and radioisotope techniques. It is found that two-thirds of the total decrease in the amount of intracellular osmolytes in apoptotic cells is accounted for by monovalent ions and one-third consists of other intracellular osmolytes. A decrease in the amount of monovalent ions results from a decrease in the amount of K+ and Cl and an increase in the Na+ content. The rate of 36Cl, Rb+ (K+), and 22Na+ equilibration between cells and the medium was found to significantly exceed the rate of apoptotic change in the cellular ion content, which indicates that unidirectional influxes and effluxes during apoptosis may be considered as being in near balance. The drift of the ion flux balance in apoptosis caused by 0.2 μM staurosporine was found to be associated with the increased ouabain-resistant Rb+ (K+) channel influx and insignificantly altered the ouabain-sensitive pump influx. Severe apoptosis induced by 1 μM staurosporine is associated with reduced pump fluxes and slightly changed channel Rb+ (K+) fluxes. In apoptotic cells, the 1.4–1.8-fold decreased Cl level is accompanied by a 1.2–1.6-fold decreased flux.  相似文献   

15.
Osmotic swelling of fish erythrocytes activates a broad-specificity permeation pathway that mediates the volume-regulatory efflux of taurine and other intracellular osmolytes. This pathway is blocked by inhibitors of the erythrocyte band 3 anion exchanger, raising the possibility that band 3 is involved in the volume-regulatory response. In this study of eel erythrocytes, a quantitative comparison of the pharmacology of swelling-activated taurine transport with that of band 3-mediated SO2− 4 transport showed there to be significant differences between them. N-ethylmaleimide and quinine were effective inhibitors of swelling-activated taurine transport but caused little, if any, inhibition of band 3. Conversely, DIDS was a more potent inhibitor of band 3-mediated SO2− 4 flux than of swelling-activated taurine transport. In cells in isotonic medium, pretreated then co-incubated with 0.1 mm DIDS, the band 3-mediated transport of SO2− 4 and Cl was reduced to a low level. Exposure of these cells to a hypotonic medium containing 0.1 mm DIDS was followed by the activation of a Cl permeation pathway showing the same inhibitor sensitivity as swelling-activated taurine transport. The data are consistent with swelling-activated transport of taurine and Cl being via a common pathway. A comparison of the swelling-activated transport rates for taurine and Cl with those for several other solutes was consistent with the hypothesis that this pathway is an anion-selective channel, similar to those that mediate the volume-regulatory efflux of Cl and organic osmolytes from mammalian cells. Received: 7 July 1995/Revised: 2 September 1995  相似文献   

16.
The mechanism of volume regulation in hypotonic media was analysed in human peripheral blood mononuclear (PBM) cells. Electronic cell sizing showed that hypotonic swelling is followed by a regulatory volume decrease (RVD) phase. This was confirmed by both electron microscopy and by cellular water determinations. The rate of regulatory shrinking was proportional to the degree of hypotonicity in the 0.5–0.9 X isotonic range. Cell viability was only marginally affected in this range. The content of cellular K+ decreased during RVD, while Na+ content remained unchanged. Similarly, the efflux of 86Rb (used as a K+ analog) increased upon dilution, whereas 22Na efflux was not altered. 86Rb uptake was enhanced by hypotonic stress and both ouabain-sensitive and -insensitive components were affected. A ouabain-sensitive stimulation was also seen in Na+- free media. Ouabain partially inhibited RVD only if added to the cells hours before hypotonic challenge. A normal shrinking response was observed in K+-free media, and also in Na+-free media when Li+, choline+, or Tris+ were the substitutes. In high K+ or Rb+ hypotonic media shrinking was absent and a second swelling phase was observed. Cs+ displayed an intermediate behavior, with shrinking observed at lower dilutions and secondary swelling at higher ones. The direction and magnitude of the response also changed when the external K+ concentration was varied and, with 50 mM K+, no regulatory volume change occurred following hypotonic stress. These findings suggest that RVD occurs largely by a passive loss of cellular K+, resulting from a selective increase in permeability to this ion. In addition, the (Na-K) pump appears to be activated upon cell swelling by a mechanism other than Na+ entry into the cell, but this activation is not essential for RVD.  相似文献   

17.
The possible correlation between P-glycoprotein (PGP) and volume-sensitive Cl channel was examined in a pair of cell lines: a subline of the human epidermoid KB cell (KB-3-1) and the corresponding MDR1-transfected cell line (KB-G2). Western blot analysis and indirect immunofluorescence studies indicated that KB-G2, but not KB-3-1, exhibits the PGP expression. Patch-clamp whole-cell recordings showed that osmotic swelling activates Cl currents not only in PGP-expressing but also in PGP-lacking cells. The amplitude of the maximal current was indistinguishable between both cells. Activation of protein kinase C (PKC) or loading with a PKC inhibitor failed to affect the swelling-induced activation of the Cl currents in both cells. The relation between whole-cell Cl currents and cell size measured simultaneously showed that volume sensitivity of the Cl channel was augmented by the PGP expression irrespective of the activity of PKC on the plasma membrane. A similar increase in volume sensitivity of the Cl channel was also induced by the expression of the ATP hydrolysis-deficient PGP mutant, K433M. We conclude that P-glycoprotein does not represent the volume-sensitive Cl channel but that its expression modulates volume sensitivity of the Cl channel in a manner independent of its ATPase activity or of the protein kinase C activity. Received: 25 September 1996/Revised: 12 December 1996  相似文献   

18.
The mechanisms controlling the volume-regulated anion current (VRAC) are incompletely elucidated. Here, we investigate the modulation of VRAC by cellular cholesterol and the potential involvement of F-actin, Rho, Rho kinase, and phosphatidylinositol-(4,5)-bisphosphate [PtdIns(4,5)P2] in this process. In Ehrlich-Lettre ascites (ELA) cells, a current with biophysical and pharmacological properties characteristic of VRAC was activated by hypotonic swelling. A 44% increase in cellular cholesterol content had no detectable effects on F-actin organization or VRAC activity. A 47% reduction in cellular cholesterol content increased cortical and stress fiber-associated F-actin content in swollen cells. Cholesterol depletion increased VRAC activation rate and maximal current after a modest (15%), but not after a severe (36%) reduction in extracellular osmolarity. The cholesterol depletion-induced increase in maximal VRAC current was prevented by F-actin disruption using latrunculin B (LB), while the current activation rate was unaffected by LB, but dependent on Rho kinase. Rho activity was decreased by 20% in modestly, and 50% in severely swollen cells. In modestly swollen cells, this reduction was prevented by cholesterol depletion, which also increased isotonic Rho activity. Thrombin, which stimulates Rho and causes actin polymerization, potentiated VRAC in modestly swollen cells. VRAC activity was unaffected by inclusion of a water-soluble PtdIns(4,5)P2 analogue or a PtdIns(4,5)P2-blocking antibody in the pipette, or neomycin treatment to sequester PtdIns(4,5)P2. It is suggested that in ELA cells, F-actin and Rho-Rho kinase modulate VRAC magnitude and activation rate, respectively, and that cholesterol depletion potentiates VRAC at least in part by preventing the hypotonicity-induced decrease in Rho activity and eliciting actin polymerization. cell swelling; kinase; phospholipid phosphatidylinositol-(4,5)-bisphosphate; cytoskeleton  相似文献   

19.
Apoptosis is an essential process in organ development, tissue homeostasis, somatic cell turnover, and the pathogenesis of degenerative diseases. Apoptotic cell death occurs in response to a variety of stimuli in physiological and pathological circumstances. Efflux of K+ and Cl leads to apoptotic volume decrease (AVD) of the cell. Both mitochondrion-mediated intrinsic, and death receptor-mediated extrinsic, apoptotic stimuli have been reported to rapidly activate Cl conductances in a large variety of cell types. In epithelial cells and cardiomyocytes, the AVD-inducing anion channel was recently determined to be the volume-sensitive outwardly rectifying (VSOR) Cl channel which is usually activated by swelling under non-apoptotic conditions. Blocking the VSOR Cl channel prevented cell death in not only epithelial and cardiac cells, but also other cell types, by inhibiting the induction of AVD and subsequent apoptotic events. Ischemia-reperfusion-induced apoptotic death in cardiomyocytes and brain neurons was also prevented by Cl channel blockers. Furthermore, cancer cell apoptosis induced by the anti-cancer drug cisplatin was recently found to be associated with augmented activity of the VSOR Cl channel and to be inhibited by a Cl channel blocker. The apoptosis-inducing VSOR Cl channel is distinct from ClC-3 and its molecular identity remains to be determined.  相似文献   

20.
Cisplatin is a widely used platinum-based anticancer drug in the chemotherapy of numerous human cancers. However, cancer cells acquire resistance to cisplatin. So far, functional loss of volume-sensitive outwardly rectifying (VSOR) Cl channels has been reported to contribute to cisplatin resistance of cancer cells. Here, we analyzed protein expression patterns of human epidermoid carcinoma KB cells and its cisplatin-resistant KCP-4 cells. Intriguingly, KB cells exhibited higher β-actin expression and clearer actin filaments than KCP-4 cells. The β-actin knockdown in KB cells decreased VSOR Cl currents and inhibited the regulatory volume decrease (RVD) process after cell swelling. Consistently, KB cells treated with cytochalasin D, which depolymerizes actin filaments, showed smaller VSOR Cl currents and slower RVD. Cytochalasin D also inhibited cisplatin-triggered apoptosis in KB cells. These results suggest that the disruption of actin filaments cause the dysfunction of VSOR Cl channels, which elicits resistance to cisplatin in human epidermoid carcinoma cells.  相似文献   

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