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)

The recently described family of proteins, the endothelins, are produced in neurons and bind to extravascular sites in the CNS. To characterize these receptors, we carried out studies on cultures of fetal rat diencephalic glia. Scatchard analysis of saturation binding studies was done for astrocytes (greater than 95% glial fibrillary acidic protein positive). For endothelin 3 (ET-3) and ET-1, respectively, a single receptor class of KD 0.41 +/- 0.05 and 0.62 +/- 0.04 nM and a receptor density of 42 +/- 0.8 and 58 +/- 1.1 fmol/mg of glial protein was found. Bound and cross-linked 125I-ET-3 or ET-1 showed a single predominant receptor band at Mr 52,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis; a minor band at 50,000 was also seen. At concentrations equal to the receptor KD, the major brain form of ET, ET-3, stimulated a nearly 200% increase in the incorporation of tritiated thymidine into glia. ET-3 and ET-1 significantly impaired the ability of atrial natriuretic peptide (ANP) to generate cyclic GMP, and isoproterenol to generate cyclic AMP. The ability of ET to inhibit ANP-induced cyclic GMP generation was reversed by cycloheximide and actinomycin-D, whereas the inhibition of isoproterenol-induced cyclic AMP generation was partially and significantly blocked by inhibitors of calcium influx, protein kinase C action, or G protein activation, as well. Astrocytes from this part of the brain are a potential target cell for endothelin, assuming these findings are present in vivo. This neuropeptide may serve as a growth stimulator for astrocytes and modulator of the actions of catecholamines or ANP on glia by inhibiting second messenger generation.
 ...
PMID:Endothelin receptors on cultured fetal rat diencephalic glia. 130 67

Studies were performed to examine the regulation of atrial natriuretic peptide- (ANP) stimulated guanylate cyclase in the the inner medulla. Primary cultures of rat inner medullary collecting tubular cells exposed to 10(-7) M ANP increased cGMP formation to 31.2 +/- 1.8 compared to the basal production of 2.1 +/- 0.6 fm/micrograms protein. This response did not appear to be transduced via a Gi protein, as preincubation with pertussis toxin did not alter the response to 10(-7) M ANP, and saponized cells exposed to 10 microM GTP gamma S did not enhance the response to ANP (77.3 +/- 5.9 vs. 86.7 +/- 6.3 g/micrograms). Likewise, changes in extracellular Ca2+ from 0.5 to 3.0 mM, decrements in intracellular Ca2+ with EGTA or increments in intracellular Ca2+ with ionomycin (5 microM) did not significantly alter the response to ANP. Neither activation of protein kinase A with forskolin (36.5 +/- 5.1) nor of protein kinase C with s,n-1,2-dioctanoylglycerol (33.2 +/- 2.5) altered the response to 10(-7) M ANP (32.2 +/- 3.3, NS). As the inner medullary environment was hypertonic, the effect of altering tonicity was studied. Cells grown for 48 hours in hypertonic media (600 mOsm/kg H2O) displayed enhanced response to 10(-8) and 10(-7) M ANP when osmolality was raised by either Na+ alone or in combination with urea, but not by urea alone. Our studies demonstrate that ANP-stimulated guanylate cyclase is insensitive to alterations in either intra- or extracellular Ca2+, is not subject to inhibition by protein kinase, and does not involve a pertussis-sensitive G protein.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Regulation of atrial natriuretic peptide-stimulated cGMP production in the inner medulla. 131 78

At least two types of receptors for natriuretic peptides have been reported: biologically active receptors coupled with guanylate cyclase (atrial natriuretic peptide [ANP]-B receptors) and clearance receptors (ANP-C receptors). To elucidate the role of protein kinase C (PKC) in the regulation of ANP-B receptors, vascular smooth muscle cells in culture were treated with phorbol ester. Incubation with receptor agonists and phorbol ester led to the desensitization of receptor-mediated cyclic guanosine monophosphate (ANP-B receptor response) in rat vascular smooth muscle cells. Although a PKC inhibitor and downregulation of PKC by long-term incubation of cells with phorbol esters blocked the phorbol ester-induced desensitization of the ANP-B receptor response, they did not block the ANP-induced desensitization of the ANP-B receptor response. In addition, when desensitization by phorbol esters was observed, ANP was still capable of desensitization. These observations suggest that the mechanism for regulating ANP-B receptor sensitivity may be both PKC-dependent and PKC-independent and mediated by phorbol esters and ANP, respectively.
 ...
PMID:Phorbol ester and atrial natriuretic peptide receptor response on vascular smooth muscle. 134 39

The heat-stable enterotoxin of Escherichia coli (STa) stimulates membrane-bound guanylate cyclase in intestinal epithelium and induces fluid and ion secretion. Using the T84 human colon carcinoma cell line as a model, we observed that phorbol esters markedly enhanced STa-stimulated cyclic GMP accumulation in T84 cells (C. S. Weikel, C. L. Spann, C. P. Chambers, J. K. Crane, J. Linden, and E. L. Hewlett, Infect. Immun. 58:1402-1407, 1990). In this study we document that the phorbol ester treatment increases 125I-STa-binding sites as well as membrane-bound guanylate cyclase activity in T84 cells and provide evidence that both effects are mediated by phosphorylation. Guanylate cyclase activity was increased approximately 50% in membranes prepared from intact T84 cells treated with phorbol-12,13-dibutyrate (beta-PDB) and after treatment of homogenates with beta-PDB in a manner dependent on ATP, MgCl2, and cytosol. Similarly, treatment of membranes with purified bovine brain protein kinase C in the presence of appropriate cofactors and beta-PDB resulted in an increase in STa-stimulated guanylate cyclase activity of about 70%. Likewise, the number of 125I-STa-binding sites was increased by about 25 to 40% in membranes prepared from intact cells or homogenates treated with beta-PDB; no effect on binding affinity (Kd = 0.15 nM) was noted. These experiments suggest that protein kinase C may phosphorylate the STa receptor-guanylate cyclase or a closely related protein and increase guanylate cyclase activity. The stimulatory effects of protein kinase C on STa-sensitive guanylate cyclase are opposite in direction to the profound inhibitory effects of the kinase on atrial natriuretic peptide-stimulated guanylate cyclase, demonstrating differential regulation by protein kinases within the guanylate cyclase-receptor family.
 ...
PMID:Regulation of intestinal guanylate cyclase by the heat-stable enterotoxin of Escherichia coli (STa) and protein kinase C. 136 Apr 49

The inner medullary collecting duct is a complex tissue that exhibits a variety of hormone signaling systems. These include the following: adenylyl cyclase activity stimulated by vasopressin (AVP), beta-adrenergic agonists, or prostanoids and inhibited by alpha 2-adrenergic agents or adenosine; guanylate cyclase activity in response to atrial natriuretic peptide (ANP); phospholipase C activity stimulated by ANP, AVP, bradykinin, endothelin, epidermal growth factor (EGF), and muscarinic cholinergic agents; and phospholipase A2 activity stimulated by AVP, bradykinin, EGF, and endothelin. The signal transduction mechanisms for each of these hormone signaling systems is succinctly reviewed, and the interactions between different signaling pathways are discussed. Central to this interaction is the mutually inhibitory relationship between activation of adenylyl cyclase and phospholipases. Increasing cellular adenosine 3',5'-cyclic monophosphate content impairs activation of phospholipases A2 and C; conversely, stimulation of phospholipase C impairs AVP-stimulated adenylyl cyclase activity via activation of protein kinase C.
 ...
PMID:Hormone signaling systems in inner medullary collecting ducts. 136 28

It has been reported that atrial natriuretic peptide (ANP) produces inositol phosphates and diacylglycerol in vascular smooth muscle cells (VSMC). The purpose of this study is to investigate whether diacylglycerol produced by ANP affects ANP-induced cyclic GMP (cGMP) accumulation through the activation of protein kinase C. Short-term (15 min) treatment of rat aortic VSMC with protein kinase C activating phorbol 12-myristate 13-acetate (PMA, 100 nM) decreased ANP (100 nM)-induced cGMP accumulation by 34.7% in the presence of IBMX (0.5 mM). However, the long-term (24 h) treatment to decrease the activity of protein kinase C led to an enhancement of the cGMP accumulation by 69.6% compared with that of control VSMC. There were no significant differences in Bmax and Kd for ANP and ANP-dependent particular guanylyl cyclase activity between long-term PMA-treated and control VSMC. In the present study, we show that the activation of protein kinase C attenuates the cGMP accumulation induced by ANP and that down-regulation of protein kinase C results in an enhancement of the cGMP accumulation. These data are consistent with the role of protein kinase C as a negative regulator in ANP-receptor/guanylyl cyclase pathway.
 ...
PMID:Down-regulation of protein kinase C potentiates atrial natriuretic peptide-stimulated cGMP accumulation in vascular smooth-muscle cells. 136 57

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 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

Stretching of atrial myocytes stimulates atrial natriuretic peptide (ANP) secretion, but the cellular processes linking mechanical distention to ANP release are unknown. We studied whether or not protein kinase C activation by phorbol ester affects atrial stretch-induced ANP secretion using the modified perfused rat heart preparation that enabled stepwise distention of the right atrium as an experimental model for stretch-stimulated ANP release. The increase in right atrial pressure (2.65 +/- 0.13 mm Hg) was accompanied by an increase in the perfusate immunoreactive ANP (IR-ANP) concentration (from 8.3 +/- 1.1 ng/5 min to 13.9 +/- 2.0 ng/5 min, P less than 0.05, n = 14). During stretch, a slight inotropic response was observed, while heart rate and perfusion pressure remained unchanged. Increase in right atrial pressure in the presence of a phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), known to stimulate protein kinase C activity in heart cells, resulted in a significantly greater increase in the perfusate IR-ANP concentration than after vehicle infusion. The calculated ANP increase corresponding to the 2 mm Hg increase in the right atrial pressure was 1.52-fold in the control group and 1.84-fold when 10 nM TPA was infused (P less than 0.05). Infusion of TPA at a dose of 24 nM further increased the stretch-induced ANP release by causing 2.22-fold (P less than 0.01) increase in IR-ANP secretion. As judged by gel filtration chromatography, abnormal release of the large mol wt stored ANP could not account for the secretory response to phorbol ester. Additionally, a phorbol ester analog, 4 alpha-phorbol 12,13-didecanoate, which is incapable of binding to and activating protein kinase C, was inactive as an ANP secretagogue. In contrast, drugs known to increase the concentration of intracellular Ca2+ in myocytes, Bay K8644 (3 and 6 microns) and forskolin (0.14 microM), significantly inhibited the stretch-stimulated ANP release. This study shows that phorbol ester enhances atrial stretch-stimulated ANP secretion from the isolated perfused heart, suggesting that protein kinase C activity is positively coupled to the stretch-induced ANP release. The results further demonstrate the negative effect of increase in intracellular Ca2+ on stretch-induced ANP release.
 ...
PMID:Phorbol esters enhance stretch-induced atrial natriuretic peptide secretion. 169 48

We investigated the effects of nitroglycerin (NTG), atrial natriuretic peptide (ANP), and CD-349 on phorbol dibutyrate (PDBu)-induced contraction in rabbit aorta. In the presence of endothelium, both NTG (10(-8)-10(-5) M) and ANP (10(-10)-10(-7) M) inhibited the PDBu-induced contraction in a concentration-dependent manner. CD-349 (10(-8)-10(-5) M) also inhibited the PDBu-induced contraction in a concentration-dependent manner. This inhibitory effect of CD-349 was independent of the existence of endothelium. Inhibitory effects of both NTG and CD-349 but not ANP were antagonized by treatment with methylene blue. However, nifedipine (10(-5) M), nicardipine (10(-5) M), and diltiazem (10(-5) M) had little or no effect on PDBu-induced contraction. Furthermore, NTG, ANP, and CD-349 inhibited endothelin-induced contraction, which may be mediated through activation of protein kinase C. These results indicate that PDBu-induced and endothelin-induced contractions in rabbit aorta are inhibited by agents known to elevate vascular cyclic GMP content.
 ...
PMID:Protein kinase C-mediated contraction in rabbit aorta is inhibited by CD-349, a dihydropyridine derivative. 171 94


1 2 3 4 5 6 7 8 9 10 Next >>