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)

1. During osmotic swelling, cultured human small intestinal epithelial cells (Intestine 407) exhibited activation of large Cl- currents under the patch-clamp whole-cell configuration. The volume-sensitive Cl- conductance was independent of intracellular Ca2+ and cyclic AMP. 2. The anion permeability sequence of the current was SCN- > I- > Br- > Cl- > F- > gluconate-, corresponding to Eisenman's sequence I. 3. Cl- currents were instantaneously activated by command pulses in a range of -120 to +45 mV. At potentials more positive than +50 mV the current showed a time-dependent inactivation. This inactivation was accelerated by increased depolarization. The instantaneous current-voltage relationship rectified in the outward direction. 4. A stilbene-derivative Cl- channel blocker, 4-acetamido-4'-isothiocyanostilbene (SITS), inhibited the Cl- current at micromolar concentrations. SITS facilitated inactivation at positive potentials. Outward currents were more prominently suppressed by SITS than inward currents. The concentrations required for 50% inhibition (IC50) of outward and inward currents were 1.5 and 6 microM, respectively. The outward and inward currents were equally inhibited by a carboxylate analogue Cl- channel blocker, 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) or diphenylamine-2-carboxylate (DPC) at higher doses (IC50 = 25 for NPPB or 350 microM for DPC). Inactivation kinetics at large depolarizations was not affected by NPPB or DPC. 5. The Cl- current was blocked by an unsaturated fatty acid, arachidonic acid (IC50 = 8 microM). Arachidonic acid was still effective in the presence of inhibitors of lipoxygenase (nordihydroguaiaretic acid, 10 microM), cyclo-oxygenase (indomethacin, 10 microM) and protein kinase C (polymyxin B, 30 microM). The Cl- current was also sensitive to another cis unsaturated fatty acid, oleic acid, which is not a substrate for oxygenases. A trans isomer of oleate, elaidic acid, and a saturated fatty acid, palmitic acid, were ineffective. 6. Single Intestine 407 cells exposed to a hypotonic solution showed a regulatory volume decrease after initial osmotic swelling. The volume regulation was abolished by SITS, NPPB, arachidonate and oleate, but not by elaidate and palmitate. 7. It is concluded that outwardly rectifying Cl- channels, which are sensitive to arachidonic acid, are activated upon osmotic swelling and involved in the subsequent cell volume regulation.
 ...
PMID:Volume-regulatory Cl- channel currents in cultured human epithelial cells. 128 79

C-type natriuretic peptide (CNP), a recently discovered natriuretic peptide, has a potent stimulatory effect on cyclic GMP (cGMP) formation in cultured mouse astrocytes. Pretreatment of astrocytes with phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), attenuated CNP-induced cGMP responses in a dose-dependent manner, with a half-maximal inhibitory concentration of 6 nM, whereas the inactive phorbol ester analog, 4 alpha-phorbol 12,13-didecanoate, was without effect. In the presence of staurosporine, a PKC inhibitor, the inhibitory effect of PMA on CNP-stimulated cGMP production was reversed. These results suggest that PKC is an inhibitory modulator of CNP-stimulated cGMP responses in astrocytes and that CNP may interact with neuropeptides which stimulate PKC.
 ...
PMID:Activation of protein kinase C attenuates the cyclic GMP responses to C-type natriuretic peptide in cultured mouse astrocytes. 132 89

To investigate the cellular mechanism for the synthesis and secretion of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), we examined the effects of vasoactive agents on the secretion rates and gene expression of ANP and BNP in cultured rat atrial cells. Endothelin (10(-7) M, +61%), 12-O-tetradecanoylphorbol 13-acetate (TPA, 10(-6) M, +62%), the calcium ionophore A23187 (10(-6) M, +95%), and Bay K 8644 (10(-6) M, +34%) (p < 0.05 each) all increased the secretion of ANP into the culture media in a dose-dependent fashion. On the other hand, endothelin (10(-7) M, +57%) and TPA (10(-6) M, +55%) (p < 0.01 each) increased the secretion of BNP in a dose-dependent manner, whereas A23187 (10(-6) M, -45%, p < 0.001) suppressed the secretion of BNP in a dose-dependent manner, and Bay K 8644 caused no significant effects on BNP secretion. The molecular forms of intracellular ANP were exclusively gamma-ANP, whereas those of BNP were gamma-BNP and its carboxy terminal 45-amino-acid peptide, BNP-45. The ratio of media to cell contents was much higher in BNP than in ANP. Northern blot analysis revealed that both ANP mRNA and BNP mRNA levels were significantly increased by 10(-7) M endothelin (ANP mRNA, +52%; BNP mRNA, +36%; p < 0.05 each) and 5 x 10(-5) M 1-oleoyl-2-acetylglycerol (ANP mRNA, +296%; BNP mRNA, +133%; p < 0.01 each) but not by 10(-6) M A23187. Thus, the secretion of ANP is stimulated by both the elevation of [Ca2+]i and the activation of protein kinase C, whereas its synthesis is increased mainly by the activation of protein kinase C. The synthesis and secretion of BNP are augmented by the activation of protein kinase C rather than the elevation of [Ca2+]i. Furthermore, the processing and secretion of ANP and BNP may be regulated in different manners.
 ...
PMID:Cellular mechanisms for synthesis and secretion of atrial natriuretic peptide and brain natriuretic peptide in cultured rat atrial cells. 139 68

We investigated regulation of atrial natriuretic factor (ANF)-stimulated cellular cGMP accumulation (ANF-s-cGMP) in an ANF-responsive human renal cell line, SK-NEP-1. Dose-response data indicated that the EC50 for ANF(99-126) was 1.1 x 10(-9) M. Brain natriuretic peptide (10(-6) M) increased cGMP to a level indistinguishable from that of ANF (10(-6) M). [Met-(O)]ANF was only half as potent as ANF, and atriopeptin I (10(-6) M) did not increase cGMP over basal levels. Preincubation of SK-NEP-1 cells with ANF, but not atriopeptin I (API), for two hours or longer, caused a concentration-dependent down-regulation of ANF-s-cGMP. Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, and A23187 and its 4-bromo derivative, calcium ionophores, inhibited ANF-s-cGMP in a dose-dependent manner. A23187 inhibition was calcium dependent and promoted net cGMP degradation. Thirty-six hour preincubation with PMA, a procedure used to down-regulate PKC, abolished acute PMA inhibition of ANF-s-cGMP without having an effect on ANF-s-cGMP or on 4-bromo-A23187 inhibition thereof. These data indicate that PKC activation specifically inhibited ANF-s-cGMP but that PKC was not required for ANF-s-cGMP in SK-NEP-1 cells. Thus structurally related ANF peptides, protein kinase C (PKC) activators, calcium ionophores are potential modulators of ANF-s-cGMP in cells from this human renal cell line.
 ...
PMID:Phorbol and calcium decreased atriopeptin response in a human renal cell line. 164 14

We studied the effect of brain natriuretic peptide (BNP) on the accumulation of cyclic GMP and the phosphorylation and activity of tyrosine hydroxylase, compared with that of atrial natriuretic peptide (ANP), in cultured bovine adrenal medullary cells. 1. BNP as well as ANP increased cellular cyclic GMP accumulation in a concentration-dependent manner (10-1000 nmol/l). BNP (1 mumol/l) and ANP (1 mumol/l) produced a 60-fold and 30-fold increase in cyclic GMP accumulation, respectively. 2. The stimulatory effects of BNP and ANP on cyclic GMP accumulation were observed even when Ca2+ or Na+ was removed from the incubation medium. 3. 12-O-Tetradecanoylphorbol 13-acetate (TPA), an activator of protein kinase C, inhibited the stimulatory effect of BNP on cyclic GMP accumulation in a concentration-dependent manner (1-100 nmol/l). Furthermore, the BNP-induced accumulation of cyclic GMP was attenuated by forskolin (1 mumol/l), an activator of adenylate cyclase. 4. BNP (1 mumol/l) and ANP (1 mumol/l) caused a significant increase in phosphorylation and activity of tyrosine hydroxylase in the cells. 5. In digitonin-permeabilized cells, cyclic GMP (1-100 mumol/l) activated tyrosine hydroxylase in the presence of ATP and Mg2+. These results suggest that BNP stimulates the accumulation of cyclic GMP in a manner similar to that of ANP. The increased accumulation of cyclic GMP by these peptides may be negatively modulated by protein kinase C and cyclic AMP and may cause the phosphorylation and activation of tyrosine hydroxylase in cultured bovine adrenal medullary cells.
 ...
PMID:Stimulatory effects of brain natriuretic peptide on cyclic GMP accumulation and tyrosine hydroxylase activity in cultured bovine adrenal medullary cells. 167 41

Preincubation of AtT-20 mouse pituitary tumour cells with the phorbol ester PMA resulted in a concentration-dependent inhibition of CNP-stimulated cyclic GMP production. The phorbol ester analogue 4 alpha phorbol had no inhibitory effect and 24 h preincubations with PMA resulted in a characteristic down-regulation of the response indicating that the inhibitory actions were mediated via the activation of protein kinase C. Forskolin in the presence of the phosphodiesterase inhibitor IBMX stimulated intracellular cyclic AMP concentrations by up to eight fold, but did not alter basal nor CNP-stimulated cyclic GMP production. These results indicate that CNP-stimulated guanylate cyclase activity associated with the GC-B natriuretic peptide receptor expressed in AtT-20 cells is inhibited by protein kinase C.
 ...
PMID:Phorbol ester activation of protein kinase C inhibits CNP-stimulated cyclic GMP production in the mouse AtT-20 pituitary tumour cell line. 752 63

1. During osmotic swelling, cultured osteoblastic cells (ROS 17/2.8) exhibited activation of large amplitude Cl- currents in the whole-cell configuration of the patch-clamp technique. Effects of hypotonic shock on cell volume and membrane conductance were rapidly reversed on return to isotonic conditions. 2. Voltage command pulses in the range -80 to +50 mV produce instantaneous activation of Cl- currents. At potentials more positive than +50 mV the current exhibited time-dependent inactivation. The instantaneous current-voltage relationship was outwardly rectifying. 3. The anion permeability sequence of the induced current was SCN- (2.2) > i- (1.9) > Br- (1.5) > Cl- (1.0) > F- (0.8) > gluconate- (0.2). This corresponds to Eisenman's sequence I. 4. The volume-sensitive Cl- current was effectively inhibited by the Cl- channel blockers 4,4'- diisothiocyanatostilbene-2,2-disulphonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Outward currents were more effectively suppressed by DIDS than inward currents. The concentrations for 50% inhibition (IC50) of outward and inward currents were 81 and 298 microM, respectively. NPPB was equally effective at inhibiting outward and inward currents (IC50 of 64 microM). The current was relatively insensitive to diphenylamine-2-carboxylate (DPC), 500 microM producing only 22.5 +/- 4.0% inhibition. 5. Inhibitors of protein kinase A (H-89, 1 microM) and tyrosine kinase (tyrphostin A25, 200 microM) were without effect upon activation of Cl- currents in response to hypotonic shock. Under isotonic conditions, elevation of intracellular Ca2+ by ionomycin (1 microM) or activation of protein kinase C by 12-O-tetradecanoylphorbol 13-acetate (TPA, 0.1 microM) failed to evoke increases in basal Cl- conductance levels. 6. It is concluded that an outwardly rectifying Cl- conductance is activated upon osmotic swelling and may be involved in cell volume regulation of ROS 17/2.8 cells.
 ...
PMID:Characterization of a volume-sensitive chloride current in rat osteoblast-like (ROS 17/2.8) cells. 756 9

To elucidate mechanisms of glucagon-induced bicarbonate-rich choleresis, we investigated the effect of glucagon on ion transport processes involved in the regulation of intracellular pH (pHi) in isolated rat hepatocyte couplets. It was found that glucagon (200 nM), without influencing resting pHi, significantly stimulates the Cl-/HCO3- exchange activity. The effect of glucagon was associated with a sevenfold increase in cAMP levels in rat hepatocytes. The activity of the Cl-/HCO3- exchanger was also stimulated by DBcAMP + forskolin. The effect of glucagon on the Cl-/HCO3- exchange was individually blocked by two specific and selective inhibitors of protein kinase A, Rp-cAMPs (10 microM) and H-89 (30 microM), the latter having no influence on the glucagon-induced cAMP accumulation in isolated rat hepatocytes. The Cl- channel blocker, NPPB (10 microM), showed no effect on either the basal or the glucagon-stimulated Cl-/HCO3 exchange. In contrast, the protein kinase C agonist, PMA (10 microM), completely blocked the glucagon stimulation of the Cl-/HCO3- exchange; however, this effect was achieved through a significant inhibition of the glucagon-stimulated cAMP accumulation in rat hepatocytes. Colchicine pretreatment inhibited the basal as well as the glucagon-stimulated Cl-/HCO3- exchange activity. The Na+/H+ exchanger was unaffected by glucagon either at basal pHi or at acid pHi values. In contrast, glucagon, at basal pHi, stimulated the Na(+)-HCO3- symport. The main findings of this study indicate that glucagon, through the cAMP-dependent protein kinase A pathway, stimulates the activity of the Cl-/HCO3- exchanger in isolated rat hepatocyte couplets, a mechanism which could account for the in vivo induced bicarbonate-rich choleresis.
 ...
PMID:Effect of glucagon on intracellular pH regulation in isolated rat hepatocyte couplets. 763 59

Atrial, brain-type, and C-type natriuretic peptides (ANP, BNP, and CNP) act via receptors with intrinsic guanylate cyclase activity. The A-type and B-type ANP receptors are selectively activated by ANP and CNP, respectively. The anterior pituitary is a site of ANP production and action, suggesting a local regulatory function, and this may also hold true for CNP which is found at its highest tissue concentrations in the anterior pituitary. Here we show that these peptides all cause dose-dependent increases in cGMP accumulation in alpha T3-1 cells (a gonadotrope-derived cell line), GH3 cells, and in primary cultures of rat pituitary cells. The response to CNP is particularly robust in alpha T3-1 cells (59 +/- 9-fold increase, EC50 14 +/- 3 nM), and the rank order of potency in alpha T3-1 cells and primary cultures (CNP >> ANP > BNP) is suggestive of action exerted via B-type receptors. Although CNP did not alter GnRH-stimulated LH release or [3H]inositol phosphate accumulation, GnRH reduced CNP-stimulated cGMP accumulation dose dependently (EC50 approximately 0.1 nM). This inhibition reflects the ability of GnRH to shift the CNP dose-response curve rightward (increasing the EC50 for CNP action approximately 10-fold both with and without 3-isobutyl-1-methylxanthine). The inhibitory effect was not blocked by omission of extracellular Ca++ nor mimicked by the Ca++ ionophore A23187 but was mimicked by a protein kinase C (PKC)-activating phorbol ester (which had a comparable effect to GnRH on the EC50 for CNP action). The data imply that CNP rather than (or in addition to) ANP may have a local regulatory function within the pituitary, that although its role is currently unknown it may involve functional interaction with GnRH in gonadotropes, and that the effect of GnRH on CNP action may be PKC-mediated. Moreover, we suggest that alpha T3-1 cells may be a useful model for investigation of the cross-talk between the B-type natriuretic peptide receptor-regulated signal transduction pathway and the Ca++/PKC pathway activated by ligand-stimulated hydrolysis of inositol phospholipids.
 ...
PMID:Cyclic guanosine monophosphate production in the pituitary: stimulation by C-type natriuretic peptide and inhibition by gonadotropin-releasing hormone in alpha T3-1 cells. 768 40

Transport defects by retinal pigment epithelial (RPE) and other cells are observed in experimental models of diabetes mellitus. Recent studies have established that glucose concentration, per se, is the critical risk factor in the pathogenesis of diabetic complications. This study was designed to test whether transport alterations could be produced in the simplest model of diabetes, sustained exposure of cultured cells to a high-glucose environment. The regulatory transport responses to acute changes in cell volume were measured in order to assess the effects of glucose on a range of transport processes. Continuous lines of nontransformed human retinal pigment epithelial (hRPE) cells were grown for two weeks with either 5.6 low glucose (LG) or 26.0 high glucose (HG) mM in paired experiments. The cell volumes of suspended cells were studied in hypo-, iso- and hypertonic solutions containing the same ionic composition. Hypotonic swelling triggered a regulatory volume decrease (RVD), inhibited by reducing the chemical driving force for K+ efflux, or blocking K+ channels (with Ba2+) or Cl- channels (with NPPB). Thus, the RVD of the hRPE cells likely reflects efflux of K+ and Cl- through parallel channels. Shrinkage caused a regulatory volume increase (RVI), which was inhibited by blocking Na+/H+ (with dimethylamiloride) or Cl-/HCO3- exchange (with DIDS). Bumetanide inhibited the RVI significantly only when the K+ concentration was increased above the baseline level. Therefore, the RVI under our baseline conditions likely reflects primarily Na+/H+ and Cl-/HCO3- antiport exchange. Growth in high-glucose medium had no substantial effect on the RVD, but reduced the rate constant of the RVI by approximately 50%. The RVI was unaffected by growth in high-mannitol medium. Stimulation of protein kinase C (PKC) with DiC8 increased the RVI of HG-cells, but not of LG-cells. The DiC8-induced stimulation was bumetanide insensitive and abolished by 1 mM amiloride. Other transport effects of PKC (on the RVD) were unaltered in the HG-cells. We conclude that sustained elevation of extracellular glucose, per se, can downregulate the Na+/H+ antiport of target cells, an effect noted in streptozotocin-treated rats, and that this downregulation does not reflect interruption of the PKC-signaling pathway.
 ...
PMID:Prolonged incubation with elevated glucose inhibits the regulatory response to shrinkage of cultured human retinal pigment epithelial cells. 807 83


1 2 3 4 5 6 7 8 Next >>