Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phytohemagglutinins are widely distributed in common food items. They constitute a heterogeneous group of proteins, which are often resistant to proteolysis in the gastrointestinal tract. Upon binding to the luminal membrane of intestinal cells, they can interfere with digestive, protective or secretory functions of the intestine. Phytohemagglutinins present in red kidney beans and jackbeans have been shown to induce diarrhea and hypersecretion in human airways, but the underlying mechanisms remain obscure. We examined how agglutinins from wheat germ (WGA), soy bean (SBA), red kidney beans (Pha-E, Pha-L), and jackbeans (Con-A) affect ion transport in mouse airways and large intestine using Ussing chamber techniques. We found that Pha-E, Pha-L, and Con-A but not WGA and SBA inhibit electrogenic Na(+) absorption dose dependently in both colon and trachea. The inhibitory effects of Con-A on Na(+) absorption were suppressed by the sugar mannose, by inhibition of phospholipase C (PLC) and protein kinase C (PKC). Thus, nutritional phytohemagglutinins block salt absorption in a PLC- and PKC-dependent manner, probably by inhibition of the epithelial Na(+) channel (ENaC). This effect may be therapeutically useful in patients suffering from cystic fibrosis.
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PMID:Effects of dietary lectins on ion transport in epithelia. 1523 2

Stimulation of purinergic receptors inhibits amiloride-sensitive Na+ transport in epithelial tissues by an unknown mechanism. Because previous studies excluded the role of intracellular Ca2+ or protein kinase C, we examined whether purinergic regulation of Na+ absorption occurs via hydrolysis of phospholipid such as phosphatidylinositol-bisphosphates (PIP2). Inhibition of amiloride-sensitive short-circuit currents (Isc-Amil) by adenine 5'-triphosphate (ATP) in native tracheal epithelia and M1 collecting duct cells was suppressed by binding neomycin to PIP2, and recovery from ATP inhibition was abolished by blocking phosphatidylinositol-4-kinase or diacylglycerol kinase. Stimulation by ATP depleted PIP2 from apical membranes, and PIP2 co-immunoprecipitated the beta subunit of ENaC. ENaC was inhibited by ATP stimulation of P2Y2 receptors in Xenopus oocytes. Mutations in the PIP2 binding domain of betaENaC but not gammaENaC reduced ENaC currents without affecting surface expression. Collectively, these data supply evidence for a novel and physiologically relevant regulation of ENaC in epithelial tissues. Although surface expression is controlled by its C terminus, N-terminal binding of betaENaC to PIP2 determines channel activity.
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PMID:Purinergic inhibition of the epithelial Na+ transport via hydrolysis of PIP2. 1550 51

Coagulation is an emerging area of interest in the pathogenesis and treatment of acute lung injury. Concentrations of the edemagenic coagulation protease thrombin are elevated in plasma and lavage fluids from afflicted patients. We explored the impact of thrombin on the formation and resolution of alveolar edema. Intravascularly applied thrombin inhibited active transepithelial 22Na transport in intact rabbit lungs, suppressing alveolar fluid clearance. Epithelial permeability was unaffected, whereas endothelial permeability was increased. In A549 human lung epithelial cells and in mouse primary alveolar type II cells, thrombin blocked ouabain-sensitive Na+,K+-ATPase-mediated 86Rb+ uptake, without altering amiloride-sensitive sodium currents. Furthermore, thrombin downregulated cell-surface expression of Na+,K+-ATPase, but not ENaC alpha and beta subunits. The endocytosis inhibitor phalloidin oleate blocked all thrombin-induced effects on sodium transport activity. Similarly, diphenyleneiodonium chloride, an inhibitor of reactive oxygen radical production, as well as a protein kinase C-zeta inhibitor, prevented these thrombin-induced effects. Thus, thrombin signaling via reactive oxygen species and protein kinase C-zeta promotes Na+,K+-ATPase endocytosis, resulting in loss of function. We propose here a dual role for thrombin in mediating disturbances to fluid balance in the lung: thrombin concomitantly provokes edema formation by increasing endothelial permeability, and inhibits alveolar edema resolution by blocking Na+,K+-ATPase function.
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PMID:Thrombin impairs alveolar fluid clearance by promoting endocytosis of Na+,K+-ATPase. 1617 51

The A663T polymorphism of the alpha-subunit of the human epithelial sodium channel (hENaC) increases the functional and surface expression of alphabetagamma-hENaC in Xenopus laevis oocytes. The context of this residue in the COOH terminus of alpha-hENaC is important for this effect, as a homologous change in murine ENaC (mENaC), A692T, does not alter functional and surface expression of mENaC. Query of a phosphoprotein database suggested that the alpha-T663 residue might be phosphorylated by PKCdelta. General inhibition of PKC with calphostin C decreased the functional and surface expression of alphaT663-hENaC and not alphaA663-hENaC, and was without effect on alphaA692-mENaC, alphaT692-mENaC, and a chimeric m(1-678)/h(650-669)alphaT663, mbetagamma-ENaC. These data suggest that residues outside of the alpha-hENaC COOH terminus are important for modulation of alphaT663-hENaC trafficking by PKC. In contrast, expression of PKCdelta decreased the functional and surface expression of alphaT663-hENaC and the functional expression of m(1-678)/h(650-669)alphaT663, mbetagamma-ENaC, and was without effect on alphaA663-hENaC, alphaA692-mENaC, or alphaT692-mENaC. PKCdelta did not phosphorylate the COOH terminus of either alphaT663-hENaC or alphaA663-hENaC in vitro, suggesting that it acts indirectly to regulate hENaC trafficking. alphaT663-hENaC was retrieved from the oocyte membrane more slowly than alphaA663-hENaC, and calphostin C increased the rate of alphaT663-hENaC removal from the oocyte membrane to a rate similar to that of alphaA663-hENaC. In contrast, PKCdelta did not alter the rate of removal of alphaT663-hENaC from the oocyte membrane, suggesting that PKCdelta altered rates of alphaT663-hENaC biosynthesis and/or delivery to the plasma membrane. These data are consistent with PKC isoform-specific effects on the intracellular trafficking of alphaT663- vs. alphaA663-hENaC.
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PMID:Differential modulation of a polymorphism in the COOH terminus of the alpha-subunit of the human epithelial sodium channel by protein kinase Cdelta. 1617 65

Recent reports have shown that cytokines inhibit fluid absorption by suppressing Na(+) channel activity in various epithelia. In this study, we investigated the role of epithelial sodium channel (ENaC) in fluid absorption in normal human middle ear epithelial (NHMEE) cells, as well as the effects of Interleukin (IL)-1beta on ENaC expression and fluid absorption in NHMEE cells. We confirmed that ENaC alpha, beta and gamma were predominantly expressed on the apical surface of the NHMEE cells by immunocytochemistry. Addition of amiloride, a potent ENaC blocker, to apical membranes of NHMEE cells decreased the fluid absorption rate in a dose-dependent manner. Treatment with 10 ng/ml IL-1beta for 24 h suppressed ENaC beta expression, the ENaC-dependent short-circuit current (Isc), and ENaC-dependent fluid absorption. When the NHMEE cells were pretreated with a phospholipase C (PLC)inhibitor (U73122, 10 microM), a protein kinase C (PKC) inhibitor (Calphostin C, 0.1 microM), or extracellular signal regulated kinase (ERK) 1/2 inhibitor (PD98059, 10 microM), the amiloride-sensitive currents in IL-1beta-treated cells were reversed to control levels; an effect not seen with SB202190 (an inhibitor of p38 mitogen-activated protein (MAP) kinase) or SP600125 (a reversible inhibitor of c-Jun N-terminal kinase). In this study we showed that ENaC is essential for fluid absorption in NHMEE cells and that IL-1beta suppresses the ENaC-dependent current via the PLC-PKC-ERK1/2 pathway. These results suggest that IL-1beta may contribute to fluid retention in otitis media with effusion by changing electrolyte transport and reducing middle ear epithelial fluid absorption.
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PMID:Interleukin-1beta suppresses epithelial sodium channel beta-subunit expression and ENaC-dependent fluid absorption in human middle ear epithelial cells. 1749 39

To determine whether ceramide mediates regulation of the renal epithelial sodium channel (ENaC) by tumor necrosis factor-alpha (TNF-alpha), confocal microscopy and patch-clamp experiments were performed in A6 distal nephron cells. We found that TNF-alpha (100 ng/ml) had no effect on ENaC activity and ceramide level when the cells were grown in the presence of aldosterone, but significantly inhibited ENaC and induced ceramide production after the cells were pretreated with LY 294002, an inhibitor of phosphatidylinositol 3-kinase, for 24 h. The inhibition of ENaC induced by TNF-alpha was mimicked by exogenous sphingomyelinase (0.1 U/ml) and C(2)-ceramide (50 microM), but neither C(2)-dihydroceramide, a membrane-impermeable analog of C(2)-ceramide, nor choline, and abolished by pretreatment with GF109203X, a protein kinase C (PKC) inhibitor. C(2)-ceramide failed to affect ENaC in the cells pretreated with GF109203X, but not in the cells pretreated with PD-98059, a mitogen-activated protein kinase kinase inhibitor. C(2)-ceramide induced the externalization of phosphatidylserine (PS) in control A6 cells, but not in the cells pretreated with GF109203X. Together with our previous finding that cytosolic PS maintains ENaC activity in A6 cells, these data suggest that ceramide mediates TNF-alpha inhibition of the renal ENaC via a pathway associated with PKC-dependent externalization of PS.
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PMID:Ceramide mediates inhibition of the renal epithelial sodium channel by tumor necrosis factor-alpha through protein kinase C. 1763 98

The cystic fibrosis transmembrane conductance regulator CFTR gene is found on chromosome 7 [Kerem, B., Rommens, J.M., Buchanan, J.A., Markiewicz, D., Cox, T.K., Chakravarti, A., Buchwald, M., Tsui, L.C., 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080; Riordan, J.R., Rommens, J.M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J.L., et al., 1989. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245, 1066-1073] and encodes for a 1480 amino acid protein which is present in the plasma membrane of epithelial cells [Anderson, M.P., Sheppard, D.N., Berger, H.A., Welsh, M.J., 1992. Chloride channels in the apical membrane of normal and cystic fibrosis airway and intestinal epithelia. Am. J. Physiol. 263, L1-L14]. This protein appears to have many functions, but a unifying theme is that it acts as a protein kinase C- and cyclic AMP-regulated Cl(-) channel [Winpenny, J.P., McAlroy, H.L., Gray, M.A., Argent, B.E., 1995. Protein kinase C regulates the magnitude and stability of CFTR currents in pancreatic duct cells. Am. J. Physiol. 268, C823-C828; Jia, Y., Mathews, C.J., Hanrahan, J.W., 1997. Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A. J. Biol. Chem. 272, 4978-4984]. In the superficial epithelium of the conducting airways, CFTR is involved in Cl(-) secretion [Boucher, R.C., 2003. Regulation of airway surface liquid volume by human airway epithelia. Pflugers Arch. 445, 495-498] and also acts as a regulator of the epithelial Na(+) channel (ENaC) and hence Na(+) absorption [Boucher, R.C., Stutts, M.J., Knowles, M.R., Cantley, L., Gatzy, J.T., 1986. Na(+) transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation. J. Clin. Invest. 78, 1245-1252; Stutts, M.J., Canessa, C.M., Olsen, J.C., Hamrick, M., Cohn, J.A., Rossier, B.C., Boucher, R.C., 1995. CFTR as a cAMP-dependent regulator of sodium channels. Science 269, 847-850]. In this chapter, we will discuss the regulation of these two ion channels, and how they can influence liquid movement across the superficial airway epithelium.
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PMID:Liquid movement across the surface epithelium of large airways. 1769 78

Activity of the epithelial sodium channel (ENaC) is limiting for Na(+) reabsorption at the distal nephron. Phosphoinositides, such as phosphatidylinositol 4,5-biphosphate [PI(4,5)P(2)] modulate the activity of this channel. Activation of purinergic receptors triggers multiple events, including activation of PKC and PLC, with the latter depleting plasma membrane PI(4,5)P(2). Here, we investigate regulation of ENaC in renal principal cells by purinergic receptors via PLC and PI(4,5)P(2). Purinergic signaling rapidly decreases ENaC open probability and apical membrane PI(4,5)P(2) levels with similar time courses. Moreover, inhibiting purinergic signaling with suramin rescues ENaC activity. The PLC inhibitor U73122, but not U73343, its inactive analog, recapitulates the action of suramin. In contrast, modulating PKC signaling failed to affect purinergic regulation of ENaC. Unexpectedly, inhibiting either purinergic receptors or PLC in resting cells dramatically increased ENaC activity above basal levels, indicating tonic activation of purinergic signaling in these polarized renal epithelial cells. Increased ENaC activity was associated with elevation of apical membrane PI(4,5)P(2) levels. Subsequent treatment with ATP in the presence of inhibited purinergic signaling failed to decrease ENaC activity and apical membrane PI(4,5)P(2) levels. Dwell-time analysis reveals that depletion of PI(4,5)P(2) forces ENaC toward a closed state. In contrast, increasing PI(4,5)P(2) levels above basal values locks the channel in an open state interrupted by brief closings. Thus our results suggest that purinergic control of apical membrane PI(4,5)P(2) levels is a major regulator of ENaC activity in renal epithelial cells.
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PMID:Purinergic control of apical plasma membrane PI(4,5)P2 levels sets ENaC activity in principal cells. 1791 33

Aldosterone elicits rapid physiological responses in target tissues such as the distal nephron through the stimulation of cell signaling cascades. We identified protein kinase D (PKD1) as an early signaling response to aldosterone treatment in the M1-cortical collecting duct (M1-CCD) cell line. PKD1 activation was blocked by the PKC inhibitor chelerythrine chloride and by rottlerin, a specific inhibitor of PKCdelta. The activation of PKCdelta and PKCepsilon coincided with PKD1 activation and while a complex was formed between PKD1 and PKCepsilon after aldosterone treatment, there was a concurrent reduction in PKD1 association with PKCdelta. A stable PKD1 knockdown M1-CCD-derrived clone was developed in which PKD1 expression was 90% suppressed by gene silencing with a PKD1-specific siRNA. The effect of aldosterone treatment on the subcellular distribution of enhanced cyan fluorescent protein (eCFP)-tagged epithelial sodium channel (ENaC) subunits in wild type (WT) and PKD1 suppressed cells was examined using confocal microscopy. In an untreated confluent monolayer of M1-CCD cells, alpha, beta, and gamma ENaC subunits were evenly distributed throughout the cytoplasm of WT and PKD1-suppressed cells. After 2 min treatment, aldosterone stimulated the localization of each of the ENaC subunits to discrete regions within the cytoplasm of WT cells. The translocation of eCFP-ENaC subunits in WT cells was inhibited by rottlerin and the mineralocorticoid receptor (MR) antagonist spironolactone. No subcellular translocation of eCFP-ENaC subunits was observed in PKD1-suppressed cells treated with aldosterone. These data demonstrate the involvement of a novel MR/PKCdelta /PKD1 signaling cascade in the earliest ENaC subunit intracellular trafficking events that follow aldosterone treatment.
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PMID:Aldosterone regulates rapid trafficking of epithelial sodium channel subunits in renal cortical collecting duct cells via protein kinase D activation. 1820 52

Aldosterone is an important regulator of Na(+) and K(+) transport in the distal nephron modulating the surface expression of transporters through the action of the mineralocorticoid receptor as a ligand-dependent transcription factor. Aldosterone stimulates the rapid activation of protein kinase-based signalling cascades that modulate the genomic effects of the hormone. Evidence is accumulating about the multi-factorial regulation of the epithelial sodium channel (ENaC) by aldosterone. Recent published data suggests that the activation of a novel PKC/PKD signalling pathway through the c-Src-dependent trans-activation of epidermal growth factor receptor contributes to early ENaC trafficking in response to aldosterone.
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PMID:Aldosterone-induced signalling and cation transport in the distal nephron. 1830 53


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