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.
in volume includes the opening of ion efflux pathways to Liver cell volume and intracellular ion concentrations decrease the amount of intracellular ions. 6 Solute efflux leads are maintained within a narrow physiologic range by to recovery toward basal values, a process referred to as reguregulated changes in membrane ion permeability. These latory volume decrease (RVD). [9][10][11][12] The ability to recover from studies of homozygous HTC hepatoma cells, a model cell swelling is a general property of mammalian cells, but the liver cell line, evaluate the relationship between cell volspecific mechanisms involved show substantial differences ume and membrane ion permeability, and assess the among different cell types. In liver, volume regulatory mechapossibility that cell swelling allows the efflux of the innisms appear to contribute importantly to many organ-level tracellular osmolite taurine through the opening of a functions, including bile acid secretion, bile formation, and conductive pathway. Cell swelling induced by exposure exocytosis. , and swelling has been shown to cause exposure to hypotonic solution or 2) intracellular perfuan increase in the partial membrane conductance to Cl 0 in sion with hypertonic sucrose-containing solutions actisome but not in all studies. 11,15 Thus, swelling-activated Cl 0 -vated an anion-selective current which was outwardly efflux could be due to the opening of anion channels or could rectified and showed time-dependent inactivation at debe driven by membrane hyperpolarization without a primary polarizing potentials. The current density at 080 mV inincrease in membrane Cl 0 conductance. depolarizing potentials, and are inhibited by the depletion of 1,587% { 172% of basal levels (P õ .05). Intracellular perintracellular adenosine triphosphate (ATP). [16][17][18] Cell swelling fusion with hypertonic solutions activated currents caralso stimulates the efflux of other organic solutes, including ried by anionic taurine, with an estimated taurine/Cl 0 taurine, a zwitterionic amino acid found in high concentrapermeability ratio of .88 { .17 for whole cell currents.tions in many cells including hepatocytes. 16,19,20 Swelling-actiThese studies demonstrate that the HTC membrane vated taurine efflux is inhibited by anion channel blockanion permeability is closely coupled to changes in cell ers, including 5-nitro-2-(3-phenylpropylamino)-benzoic acid volume, and that the recovery from swelling depends (NPPB), suggesting that both Cl 0 and taurine may leave the upon activation of anion-selective conductance pathcell through a common channel-mediated-mechanism. Recently, swelling-activated taurine efflux has been demHepatocytes show the facilitated uptake of a wide range of onstrated in several liver preparations. Using isotopic techorganic and inorganic solutes including bile acids, amino niques, hypotonic exposure has been shown to increase tauacids, and HCO 0 3 , which are essential for normal cell func-rine fluxes in hepatocytes from the elasmobranch Raja tion.1-4 However, the intra...
Liver cell volume and intracellular ion concentrations are maintained within a narrow physiologic range by regulated changes in membrane ion permeability. These studies of homozygous HTC hepatoma cells, a model liver cell line, evaluate the relationship between cell volume and membrane ion permeability, and assess the possibility that cell swelling allows the efflux of the intracellular osmolite taurine through the opening of a conductive pathway. Cell swelling induced by exposure to hypotonic solutions (203 mOsm) caused a rapid increase in cell volume, followed by recovery toward basal values. Volume recovery was inhibited by Cl- depletion or by exposure to the putative Cl- channel blocker 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) (25 micromol/L). Swelling increased the efflux rates of 36Cl (181% +/- 15%, P < .01) and 125I (310% +/- 21%, P < .01). In whole cell patch clamp recordings, cell swelling induced by 1) exposure to hypotonic solution or 2) intracellular perfusion with hypertonic sucrose-containing solutions activated an anion-selective current which was outwardly rectified and showed time-dependent inactivation at depolarizing potentials. The current density at -80 mV increased proportionally with increases in the transmembrane osmotic gradient from basal values of -1 pA/pF to maximal values of 70 pA/pF with 100 mmol/L sucrose in the pipette. Basal taurine permeability was low, but cell swelling increased the efflux of [1,2-3H]taurine to 1,587% +/- 172% of basal levels (P < .05). Intracellular perfusion with hypertonic solutions activated currents carried by anionic taurine, with an estimated taurine/Cl- permeability ratio of .88 +/- .17 for whole cell currents. These studies demonstrate that the HTC membrane anion permeability is closely coupled to changes in cell volume, and that the recovery from swelling depends upon activation of anion-selective conductance pathways permeable to both Cl- and taurine.
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