cAMP- and swelling-activated chloride conductance in rat hepatocytes

Meng, Xianmin; Weinman, Steven A.

doi:10.1152/ajpcell.1996.271.1.c112

Cited by 42 publications

(53 citation statements)

References 18 publications

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“…Recent studies indicate that dynamic changes in cell volume directly coordinate liver metabolic and secretory functions through effects on solute transport and gene expression, 37 and that cell volume is regulated in part by changes in membrane Cl Ϫ permeability. 16 The principal FIG. 5.…”

Section: Discussionmentioning

confidence: 99%

“…In primary hepatocytes, PKA appears to serve a modulatory function, increasing channel sensitivity through effects on the threshold or set-point for current activation. 16 However, primary increases or decreases in cell volume were able to overcome the effects of cAMP analogs, and the effect of cAMP inhibition on volume-sensitive Cl Ϫ channel opening was not assessed. 16 In our studies, the putative cAMP inhibitor, Rp-cAMPS, failed to inhibit I Cl-Swell , suggesting that PKA is not the primary signal responsible for volumesensitive current activation.…”

Section: Discussionmentioning

confidence: 99%

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Activation of protein kinase C? couples cell volume to membrane Cl? permeability in HTC hepatoma and Mz-ChA-1 cholangiocarcinoma cells

et al. 1998

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Physiological increases in liver cell volume lead to an adaptive response that includes opening of membrane Cl ؊ channels, which is critical for volume recovery. The purpose of these studies was to assess the potential role for protein kinase C (PKC) as a signal involved in cell volume homeostasis. Studies were performed in HTC rat hepatoma and Mz-ChA-1 human cholangiocarcinoma cells, which were used as model hepatocytes and cholangiocytes, respectively. In each cell type, cell volume increases were followed by: 1) translocation of PKC␣ from cytosolic to particulate (membrane) fractions; 2) a 10-to 40-fold increase in whole-cell membrane Cl ؊ current density; and 3) partial recovery of cell volume. In HTC cells, the volume-dependent Cl Liver cells play a central role in systemic metabolic balance and bile formation, with high capacities for protein synthesis, gluconeogenesis, and vectorial secretion of organic solutes and electrolytes into bile. These and other specialized functions are rapidly and precisely regulated by circulating hormones and substrate availability to meet changing physiological demands. Previous studies indicate that hormonal control of metabolic function requires selective modulation of membrane ion permeability, which changes of 10-to 50-fold following receptor stimulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of protein kinase C? couples cell volume to membrane Cl? permeability in HTC hepatoma and Mz-ChA-1 cholangiocarcinoma cells

et al. 1998

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“…As previously shown, the characteristics of this LTD 4 current were indistinguishable from those of the swelling activated current with weak outward rectification, slow inactivation at positive voltages, and blockage by 5-nitro-2-(3-phenylpropylamino) benzoic acid. 4 Pretreatment of hepatocytes with the LTD 4 receptor antagonist, MK-571, had no effect on the leukotriene-induced conductance, suggesting that the leukotriene effect was not mediated by conventional cysteinyl leukotriene receptors. 21 Interestingly, when MK-571 itself, without LTD 4 , was included in the pipet at a concentration of 10 mol/L, it also activated the chloride conductance, identical to the effect of LTD 4 (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…A reduction of the swelling threshold required for channel activation has previously been observed under several conditions. 4,26 We therefore measured the effects of Mrp2 substrates on the time course of osmotic swelling-induced chloride channel activation in untreated hepatocytes. Figure 2A shows that in normal cells there is about a 5 minute time-lag of activation after hyposmotic superfusion.…”

Section: Resultsmentioning

confidence: 99%

“…3 Chloride channel activation is a delayed process that follows swelling by a variable time lag of up to several minutes. 1,4 The pathways which lead to channel activation involve kinase-dependent signaling cascades and accessory molecules such as caveolin, 5,6 but the identity of the swelling activated chloride channels themselves remains largely unknown. 7 A perplexing characteristic of swelling activated chloride channels is the repeated observation that expression of multiple different proteins appears to influence their activity.…”

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Mrp2 modulates the activity of chloride channels in isolated hepatocytes

Weinman

2002

Hepatology

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Adenosine triphosphate binding cassette family transport proteins are important organic ion transporters in hepatocytes but these molecules may also exhibit other functions. In the present study we have measured the effects of substrates of the canalicular organic ion transporter multidrug resistance associated protein 2 (Mrp2) on chloride channel activation and cell volume regulation. We found that substrates such as leukotriene D 4 , 17-␤-estradiol glucuronide, and the leukotriene inhibitor MK-571 accelerated the activation of chloride channels by cell swelling and activated chloride channels in cytokine-pretreated hepatocytes. Two conjugated estrogens that are not Mrp2 substrates did not produce this effect. Hepatocytes derived from a strain of transport-deficient rats (TR ؊ ), which lack Mrp2 expression, showed none of these substrate effects. Coincident with their ability to activate channels, the Mrp2 substrates increased the rate of volume regulatory decrease by approximately 50% (P < .01), confirming that enhanced channel activation under this condition stimulated volume regulation. In TR-hepatocytes the Mrp2 substrate had no effect on volume regulation.

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Glycine protects against hepatocyte killing by KCN or hypoxia by preventing intracellular Na+ overload in the rat

et al. 1997

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exposed to endotoxin shock. 7 Although the cytoprotective Glycine has been shown to prevent hepatocyte death ineffect of glycine is well established, the mechanisms involved duced by anoxia and by several toxic agents. However, the still must be fully clarified. Cytoprotection by glycine, in fact, mechanisms responsible for such a cytoprotective effect have is not related to the preservation of intracellular ATP, nor not yet been entirely clarified. We have previously shown that does it require protein synthesis or mitochondrial metaboan uncontrolled increase in intracellular Na / is critical for lism of the amino acid. 1,3 Moreover, glycine does not prevent hepatocyte killing induced by adenosine triphosphate (ATP) intracellular acidification consequent to ATP depletion, 3,8 depletion. We herein report that protection by glycine (2 and it does not interfere with the accumulation of unesterimmol/L) against cytotoxicity induced in isolated rat hepatofied fatty acids in isolated renal proximal tubular cells. 9 Recyte by potassium cyanide (KCN) or hypoxia was associated cently, glycine has been shown to inhibit nonlysosomal prowith the prevention of cytosolic Na / accumulation. The additeolysis in rat hepatocytes exposed to potassium cyanide tion of the Na / ionophore, monensin, abolished the effects of (KCN) or anoxia, suggesting that it might protect against glycine on both Na / increase and cytotoxicity. Pretreating hepatocellular injury by preventing the activation of degradahepatocytes with the glycine-receptor antagonist, strychnine tive proteolytic processes. the intracellular acidification consequent to mitochondrial dysfunctions, whereas the block of Na / efflux is mainly The small, neutral amino acid, glycine, has been shown to caused by the inhibition of the Na / /K / ATPase activity conseprevent irreversible cell injury caused by adenosine triphosquent to ATP depletion. 16 Consistently, the incubation of phate (ATP) depletion in rabbit renal proximal tubular isolated hepatocytes in a bicarbonate-free buffer or in an cells, 1,2 rat hepatocytes, 3,4 and human endothelial cells. 5 acidic medium (pH 6.5) greatly reduced Na / overload and Moreover, glycine addition minimizes reperfusion injury of cell killing by the redox cycling agent, menadione, 16 which is rat liver in a low-flow/reflow liver perfusion model, 6 while known to damage mitochondria and cause ATP depletion.12 feeding a glycine-containing diet improves the survival of rat These observations have prompted us to investigate whether the cytoprotective activity of glycine against the hepatotoxic action of anoxia or KCN poisoning might be asAbbreviations: ATP, adenosine triphosphate; KCN, potassium cyanide; NPPB, 5-cribed to an effect on Na / accumulation.nitro-2-(3-phenylpropylamino) benzoic acid.

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cAMP- and swelling-activated chloride conductance in rat hepatocytes

Cited by 42 publications

References 18 publications

Activation of protein kinase C? couples cell volume to membrane Cl? permeability in HTC hepatoma and Mz-ChA-1 cholangiocarcinoma cells

Activation of protein kinase C? couples cell volume to membrane Cl? permeability in HTC hepatoma and Mz-ChA-1 cholangiocarcinoma cells

Mrp2 modulates the activity of chloride channels in isolated hepatocytes

Glycine protects against hepatocyte killing by KCN or hypoxia by preventing intracellular Na+ overload in the rat

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