Cytosolic Ca2+ and protein kinase Calpha couple cellular metabolism to membrane K+ permeability in a human biliary cell line.

Wang, Yu; Roman, Richard M.; Schlenker, Thorsten; Hannun, Yusuf A.; Raymond, John R.; Fitz, John

doi:10.1172/jci119483

Cited by 25 publications

(28 citation statements)

References 36 publications

(41 reference statements)

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“…Translocation of PKC-␣ after ischemia has also been observed by others. Wang and coworkers 25 demonstrated that PKC-␣ is responsible for the opening of ion channels with ischemia. Others 26 have found a PKC-␣ translocation in ischemic myocardium and myocardial cells.…”

Section: Discussionmentioning

confidence: 99%

Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C

et al. 1999

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Background-Dihydropyridines block calcium channels; however, they also influence endothelial cells, which do not express calcium channels. We tested the hypothesis that nifedipine can prevent ischemia-induced endothelial permeability increases by inhibiting protein kinase C (PKC) in cultured porcine endothelial cells. Methods and Results-Ischemia was induced by potassium cyanide/deoxyglucose, and permeability was measured by albumin flux. Ion channels were characterized by patch clamp. [Ca 2ϩ ] i was measured by fura 2. PKC activity was measured by substrate phosphorylation after cell fractionation. PKC isoforms were assessed by Western blot and confocal microscopy. Nifedipine prevented the ischemia-induced increase in permeability in a dose-dependent manner. Ischemia increased [Ca 2ϩ ] i , which was not affected by nifedipine. Instead, ischemia-induced PKC translocation was prevented by nifedipine. Phorbol ester also increased endothelial cell permeability, which was dose dependently inhibited by nifedipine. The effects of non-calcium-channel-binding dihydropyridine derivatives were similar. Analysis of the PKC isoforms showed that nifedipine prevented ischemia-induced translocation of PKC-␣ and PKC-. Specific inhibition of PKC isoforms with antisense oligodeoxynucleotides demonstrated a major role for PKC-␣. Conclusions-Nifedipine exerts a direct effect on endothelial cell permeability that is independent of calcium channels.The inhibition of ischemia-induced permeability by nifedipine seems to be mediated primarily by PKC-␣ inhibition. Anti-ischemic effects of dihydropyridine calcium antagonists could be due in part to their effects on endothelial cell permeability. (Circulation. 1999;99:2523-2529.)

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Section: Discussionmentioning

confidence: 99%

Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C

et al. 1999

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“…13,15 In addition, PKC␣ is the principal Ca 2ϩ -sensitive PKC isoform detected by isoform-specific antisera. 4,25 Thus, the channels and signaling pathways involved are likely to reflect those operative in primary cells. Cells were passaged at approximately weekly intervals and maintained at 37°C in 5% CO 2 using HCO 3 -containing Minimal Essential Media (Sigma, St. Louis, MO) supplemented with 2 mmol/L glutamine and 5% fetal calf serum for HTC cells, 15,28 and CMRL-1066 media (GIBCO-BRL, Grand Island, NY) supplemented with 10% heat-inactivated fetal calf serum for Mz-ChA-1 cells.…”

Section: Methodsmentioning

confidence: 99%

“…12,20,21 Protein kinase C (PKC) in particular has been shown to have either positive 22,23 or negative 24 effects on recovery from swelling depending on the cell type under investigation. Previous studies in hepatocyte and biliary cell models indicate that PKC␣ directly modulates Cl Ϫ channel activation during metabolic stress, 4,25 but the role(s) of PKC as a signal regulating liver cell volume have not been assessed. PKC␣ is the principal Ca 2ϩ -sensitive PKC isoform present in liver and biliary cell models, 4,[25][26][27] and intracellular dialysis with recombinant PKC␣ stimulates an increase in membrane ion permeability.…”

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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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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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“…Furthermore, mastoparan caused sequestration and a reduction in the activity of Rho, similar to the changes seen during ischemia. Ischemia also stimulates K ϩ channel activity in a variety of nonintestinal tissues (14,22,34,40,41 (21,31). Here we show that chemical hypoxia activates basolateral IK Ca channels in human colonic crypts, while simultaneously increasing the permeability of the colonic epithelium.…”

mentioning

confidence: 52%

“…Metabolic stress has previously been shown to activate different types of K ϩ channel in cholangiocytes and hepatocytes (40,41), vascular cells (22,34), and airway cells (14). However, the magnitude of the effects we observed in human colonic crypt cells (45% and ϳ2-fold increases in IK Ca channel activity and whole cell K ϩ conductance, respectively) were much smaller than those reported previously in human hepatoma and biliary cell lines, in which there were 40-to 70-fold increases in whole cell K ϩ conductance (40,41). On the other hand, we observed more sustained responses to chemical hypoxia in human colonic crypt cells compared with those seen in the cell lines.…”

Section: Discussionmentioning

confidence: 99%

Basolateral potassium (IK_Ca) channel inhibition prevents increased colonic permeability induced by chemical hypoxia

Loganathan

Linley

Rajput

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Loganathan A, Linley JE, Rajput I, Hunter M, Lodge JP, Sandle GI. Basolateral potassium (IKCa) channel inhibition prevents increased colonic permeability induced by chemical hypoxia. Am J Physiol Gastrointest Liver Physiol 300: G146 -G153, 2011. First published October 21, 2010 doi:10.1152/ajpgi.00472.2009.-Major liver resection is associated with impaired intestinal perfusion and intestinal ischemia, resulting in decreased mucosal integrity, increased bacterial translocation, and an increased risk of postoperative sepsis. However, the mechanism by which ischemia impairs intestinal mucosal integrity is unclear. We therefore evaluated the role of Ca 2ϩ -sensitive, intermediate-conductance (IKCa) basolateral potassium channels in enhanced intestinal permeability secondary to chemical hypoxia. The effects of chemical hypoxia induced by 100 M dinitrophenol (DNP) and 5 mM deoxyglucose (DG) on basolateral IKCa channel activity and whole cell conductance in intact human colonic crypts, and paracellular permeability (GS) in isolated colonic sheets, were determined by patch-clamp recording and transepithelial electrical measurements, respectively. DNP and DG rapidly stimulated IKCa channels in cell-attached basolateral membrane patches and elicited a twofold increase (P ϭ 0.004) in whole cell conductance in amphotericin B-permeabilized membrane patches, changes that were inhibited by the specific IKCa channel blockers TRAM-34 (100 nM) and clotrimazole (CLT; 10 M). In colonic sheets apically permeabilized with nystatin, DNP elicited a twofold increase (P ϭ 0.005) in GS, which was largely inhibited by the serosal addition of 50 M CLT. We conclude that, in intestinal epithelia, chemical hypoxia increases GS through a mechanism involving basolateral IKCa channel activation. Basolateral IKCa channel inhibition may prevent or limit increased intestinal permeability during liver surgery. Ca 2ϩ -sensitive intermediate-conductance basolateral potassium channels

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Cytosolic Ca2+ and protein kinase Calpha couple cellular metabolism to membrane K+ permeability in a human biliary cell line.

Cited by 25 publications

References 36 publications

Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C

Calcium Antagonists Ameliorate Ischemia-Induced Endothelial Cell Permeability by Inhibiting Protein Kinase C

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

Basolateral potassium (IK_Ca) channel inhibition prevents increased colonic permeability induced by chemical hypoxia

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