EC:2.7.11.13 - FACTA Search

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

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.
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PMID:Phorbol ester and atrial natriuretic peptide receptor response on vascular smooth muscle. 134 39

Astroglial cells derived from the mammalian central nervous system contain a wide variety of peptide receptors, including specific sites for angiotensin II (AII) and atrial natriuretic peptide (ANP). The AII receptors present in these cells are primarily of the AT1 subtype. The ANP receptors present in these cells consist of a mix of ANP-A and ANP-B sites ("biological receptors") and also ANP-C sites ("clearance receptors"). Available evidence indicates that activation of AII receptors results in a stimulation of astroglial proliferation, whereas ANP has an antiproliferative effect in these cells. Intracellular pathways which may mediate these effects of AII and ANP on cell proliferation are discussed, including the presentation of novel data on the activation of protein kinase C and of glucose uptake by AII. We also consider the possibility that the opposing actions of AII and ANP on astroglial proliferation may represent another facet of the mutual antagonism between these two peptides, which has been observed throughout mammalian systems.
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PMID:Peptide receptors in astroglia: focus on angiotensin II and atrial natriuretic peptide. 792 41

We determined previously that astroglia cultured from newborn rat brain contain both guanylyl cyclase-coupled and atrial natriuretic peptide (ANP)-C natriuretic peptide receptors. Here, we investigated the effects of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) on these receptor subtypes in cultured astroglia to understand the intracellular processes involved in the modulation of natriuretic peptide receptors in these cells. PMA (10 nM to 1 microM; 15 min to 24 h) treatment elicited a time- and concentration-dependent decrease in the numbers of 125I-labeled ANP specific binding sites, which was inhibited by the PKC antagonist staurosporine (500 nM). Furthermore, PMA (100 nM, 2 or 24 h) treatment elicited a significant decrease in the specific binding of 125I-des-Cys-Cys-ANP, an ANP-C receptor selective ligand. PMA (10 nM to 1 microM; 30 min) treatment also significantly decreased ANP (100 nM)-stimulated guanosine 3', 5'-cyclic monophosphate levels in cultured astroglia, an effect unmodified by phosphodiesterase inhibition. These data indicate that PKC modulates both guanylyl cyclase-coupled and ANP-C natriuretic peptide receptors in cultured astroglia.
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PMID:Protein kinase C modulates natriuretic peptide receptors in astroglial cultures from rat brain. 863 52

In the present studies, we have investigated the modulation of atrial natriuretic peptide (ANP) receptor of R2 subtype (ANP-R2/ANP-C) coupled to adenylyl cyclase/cAMP signal transduction system by angiotensin II (angII). C-ANF4-23 [des(Gln18, Ser19, Gln20, Leu21, Gly22)ANF4-23-NH2] and AngII inhibited adenylyl cyclase activity in a concentration-dependent manner in vascular smooth muscle cells (VSmc A-10). The maximal inhibitions observed were about 40 and 30%, respectively, with an apparent Ki of about 1 and 10 nm. Pretreatment of the cells with AngII resulted in the attenuation of both C-ANF4-23 and AngII-mediated inhibitions of adenylyl cyclase, without altering [125I]-ANF binding. The levels of Gialpha-2 and Gialpha-3 proteins as determined by immunoblotting were also augmented by AngII treatment. In addition, AngII treatment stimulated the phosphorylation of Gialpha2 but not of Gialpha3 or ANP-C receptor, as revealed by immunoprecipitation of the proteins using specific antibodies after prelabelling the cells with [32P]orthophosphate. Staurosporine and chelerythrine, protein kinase C (PKC) inhibitors at 1 and 100 nm, respectively, prevented the AngII-mediated desensitization of C-ANF 4-23-sensitive adenylyl cyclase. In addition, the AngII-mediated phosphorylation of Gialpha2 protein was also inhibited partially by about 35% by staurosporine treatment. These results suggest that the attenuation of C-ANF4-23-mediated inhibition of adenylyl cyclase activity by AngII may not be attributed to the downregulation of receptors or to the decreased levels of G-proteins, and may involve PKC-dependent mechanisms.
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PMID:Angiotensin II modulates ANP-R2/ANP-C receptor-mediated inhibition of adenylyl cyclase in vascular smooth muscle cells: role of protein kinase C. 973 34

The expression of the natriuretic peptide system in the human ocular ciliary epithelium (CE) and in cultured nonpigmented (NPE) ciliary epithelial cells was examined. By RT-PCR and DNA sequencing, we demonstrated that the CE and NPE cells express mRNA for (i) ANP; (ii) BNP; (iii) NPR-A, NPR-B, and NPR-C receptors; and (iv) the neutral endopeptidase 24.11. Radioimmunoassay results indicate that BNP is secreted by cultured NPE cells at much higher levels than ANP. NPR-A and NPR-B receptors elicited a cGMP response to ANP, BNP, and CNP, in a rank order of potency (CNP >> ANP >/= BNP), indicative that the NPR-B receptor is predominant in NPE cells. A71915, an inhibitor of NPR-A activity, attenuated (65-75%) cGMP response to ANP and BNP, but not to CNP. C-ANP4-23 elicited an inhibitory effect (30-37%) on basal levels of cAMP in NPE cells and on forskolin NPE-treated cells, indicative that the NPR-C receptor is functional in these cells. PMA induced, in NPE cells, a long-term downregulation (75-85%) of NPR-C receptor mRNA, but not of NPR-A or NPR-B receptor mRNA, suggesting a differential regulation of NPR-C receptor mRNA via activation of PKC. Collectively, our data provide molecular evidence that all the components of the natriuretic peptide system with the exception of CNP are coexpressed in the ocular NPE ciliary epithelial cells, where they may function as local autocrine/paracrine modulators to influence eye pressure.
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PMID:Functional expression of components of the natriuretic peptide system in human ocular nonpigmented ciliary epithelial cells. 1022 28

This study examined the ability of protein kinase C (PKC) to induce heterologous desensitization by targeting specific G proteins and limiting their ability to transduce signals in smooth muscle. Activation of PKC by pretreatment of intestinal smooth muscle cells with phorbol 12-myristate 13-acetate, cholecystokinin octapeptide, or the phosphatase 1 and phosphatase 2A inhibitor, calyculin A, selectively phosphorylated Galpha(i-1) and Galpha(i-2), but not Galpha(i-3) or Galpha(o), and blocked inhibition of adenylyl cyclase mediated by somatostatin receptors coupled to G(i-1) and opioid receptors coupled to G(i-2), but not by muscarinic M(2) and adenosine A(1) receptors coupled to G(i-3). Phosphorylation of Galpha(i-1) and Galpha(i-2) and blockade of cyclase inhibition were reversed by calphostin C and bisindolylmaleimide, and additively by selective inhibitors of PKCalpha and PKCepsilon. Blockade of inhibition was prevented by downregulation of PKC. Phosphorylation of Galpha-subunits by PKC also affected responses mediated by betagamma-subunits. Pretreatment of muscle cells with cANP-(4-23), a selective agonist of the natriuretic peptide clearance receptor, NPR-C, which activates phospholipase C (PLC)-beta3 via the betagamma-subunits of G(i-1) and G(i-2), inhibited the PLC-beta response to somatostatin and [D-Pen(2,5)]enkephalin. The inhibition was partly reversed by calphostin C. Short-term activation of PKC had no effect on receptor binding or effector enzyme (adenylyl cyclase or PLC-beta) activity. We conclude that selective phosphorylation of Galpha(i-1) and Galpha(i-2) by PKC partly accounts for heterologous desensitization of responses mediated by the alpha- and betagamma-subunits of both G proteins. The desensitization reflects a decrease in reassociation and thus availability of heterotrimeric G proteins.
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PMID:Heterologous desensitization of response mediated by selective PKC-dependent phosphorylation of G(i-1) and G(i-2). 1100 72

To identify neural tumor cell lines that could be used as models to study growth-related natriuretic peptide actions, we determined the effects of these peptides on the proliferation of human and rodent neuroblastoma cell lines. Subnanomolar concentrations of atrial natriuretic peptide (ANP) and type C natriuretic peptide (CNP) stimulated proliferation in all four cell lines. These actions were associated with cGMP elevation and were blocked by a protein kinase G inhibitor. These data imply the involvement of guanylyl cyclase (GC)-coupled natriuretic receptors. However, higher concentrations of ANP and CNP, and low concentrations of des-[Gln(18),Ser(19),Gly(20),Leu(21),Gly(22)]-ANP(4-23)-NH(2) (desANP(4-23)) (analog for NPR-C receptor) exerted antiproliferative actions in three of the cell lines. These effects were insensitive to a protein kinase G inhibitor and to HS-142-1, suggesting that growth-inhibitory actions involved a non-GC receptor. They did not appear to involve cAMP, protein kinase A, protein kinase C, or calcium mobilization but were abolished when constitutive mitogen-activated protein kinase activity was inhibited. Radioligand binding experiments revealed the presence of a uniform class of binding sites in NG108 cells and multiple binding sites in Neuro2a cells. Northern and reverse transcriptase-polymerase chain reaction analyses revealed differential gene expression for NPR-A/B/C in NG108 and Neuro2a cells. The results indicate that natriuretic peptides stimulate neuroblastoma cell proliferation through type NPR-A/B (GC) receptors. Higher concentrations of ANP and CNP exerted a mitogen-activated protein kinase-dependent antiproliferative action mediated by a non-GC receptor that interacts with desANP(4-23) with relatively high affinity.
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PMID:Proliferative actions of natriuretic peptides on neuroblastoma cells. Involvement of guanylyl cyclase and non-guanylyl cyclase pathways. 1155 33

Atrial natriuretic peptide (ANP) reduces ischemia and/or reperfusion damage in several organs, but the mechanisms involved are largely unknown. We used freshly isolated rat hepatocytes to investigate the mechanisms by which ANP enhances hepatocyte resistance to hypoxia. The addition of ANP (1 micromol/L) reduced the killing of hypoxic hepatocytes by interfering with intracellular Na(+) accumulation without ameliorating adenosine triphosphate (ATP) depletion and pH decrease caused by hypoxia. The effects of ANP were mimicked by 8-bromo-guanosine 3', 5'-cyclic monophosphate (cGMP) and were associated with the activation of cGMP-dependent kinase (cGK), suggesting the involvement of guanylate cyclase-coupled natriuretic peptide receptor (NPR)-A/B ANP receptors. However, stimulating NPR-C receptor with des-(Gln(18), Ser(19),Gly(20),Leu(21),Gly(22))-ANP fragment 4-23 amide (C-ANP) also increased hepatocyte tolerance to hypoxia. C-ANP protection did not involve cGK activation but was instead linked to the stimulation of protein kinase C (PKC)-delta through G(i) protein- and phospholipase C-mediated signals. PKC-delta activation was also observed in hepatocytes receiving ANP. The inhibition of phospholipase C or PKC by U73122 and chelerythrine, respectively, significantly reduced ANP cytoprotection, indicating that ANP interaction with NPR-C receptors also contributed to cytoprotection. In ANP-treated hepatocytes, the stimulation of both cGK and PKC-delta was coupled with dual phosphorylation of p38 mitogen-activated protein kinase (MAPK). The p38 MAPK inhibitor SB203580 abolished ANP protection by reverting p38 MAPK-mediated regulation of Na(+) influx by the Na(+)/H(+) exchanger. In conclusion, ANP recruits 2 independent signal pathways, one mediated by cGMP and cGK and the other associated with G(i) proteins, phospholipase C, and PKC-delta. Both cGK and PKC-delta further transduce ANP signals to p38 MAPK that, by maintaining Na(+) homeostasis, are responsible for ANP protection against hypoxic injury.
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PMID:Mechanisms of hepatocyte protection against hypoxic injury by atrial natriuretic peptide. 1254 Jul 77

Phosphorylation of Ser19 on the 20-kDa regulatory light chain of myosin II (MLC20) by Ca2+/calmodulin-dependent myosin light-chain kinase (MLCK) is essential for initiation of smooth muscle contraction. The initial [Ca2+]i transient is rapidly dissipated and MLCK inactivated, whereas MLC20 and muscle contraction are well maintained. Sustained contraction does not reflect Ca2+ sensitization because complete inhibition of MLC phosphatase activity in the absence of Ca2+ induces smooth muscle contraction. This contraction is suppressed by staurosporine, implying participation of a Ca2+-independent MLCK. Thus, sustained contraction, as with agonist-induced contraction at experimentally fixed Ca2+ concentrations, involves (a) G protein activation, (b) regulated inhibition of MLC phosphatase, and (c) MLC20 phosphorylation via a Ca2+-independent MLCK. The pathways that lead to inhibition of MLC phosphatase by G(q/13)-coupled receptors are initiated by sequential activation of Galpha(q)/alpha13, RhoGEF, and RhoA, and involve Rho kinase-mediated phosphorylation of the regulatory subunit of MLC phosphatase (MYPT1) and/or PKC-mediated phosphorylation of CPI-17, an endogenous inhibitor of MLC phosphatase. Sustained MLC20 phosphorylation is probably induced by the Ca2+-independent MLCK, ZIP kinase. The pathways initiated by G(i)-coupled receptors involve sequential activation of Gbetagamma(i), PI 3-kinase, and the Ca2+-independent MLCK, integrin-linked kinase. The last phosphorylates MLC20 directly and inhibits MLC phosphatase by phosphorylating CPI-17. PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC2 and NPR-C), inhibit adenylyl and guanylyl cyclase activities, and stimulate cAMP-specific PDE3 and PDE4 and cGMP-specific PDE5 activities. These kinases also act downstream to inhibit (a) initial contraction by inhibiting Ca2+ mobilization and (b) sustained contraction by inhibiting RhoA and targets downstream of RhoA. This increases MLC phosphatase activity and induces MLC20 dephosphorylation and muscle relaxation.
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PMID:Signaling for contraction and relaxation in smooth muscle of the gut. 1646 Feb 76

C-type natriuretic peptide (CNP) is produced by the vascular smooth muscle cells (SMCs) of injured and atherosclerotic arteries, in which it may exert autocrine control over SMCs by binding to its principal receptors, NPR-B and NPR-C, but few studies have examined the factors that regulate CNP expression in human SMCs. In the present report, we show that serum induces significant increases in both CNP and NPR-C transcript levels in human, but not rat SMCs in culture, and that pretreatment with either the general tyrosine kinase inhibitor genistein, the platelet-derived growth factor (PDGF) tyrosine kinase inhibitor AG 1296, or the protein kinase C (PKC) inhibitor GF109203X blocks most of the serum-induced increase in CNP. PDGF-BB also induced significant dose-dependent increases in CNP transcript that correlated temporally with the serum effect on CNP mRNA. Inhibition of several PDGF-BB signaling pathways downstream of receptor activation showed that PKC inhibition with GF109203X was almost as effective as genistein in abolishing the PDGF-BB-induced up-regulation of CNP mRNA. Furthermore, PKC activation by phorbol 12-myristate 13-acetate (PMA) produced an extremely high level of CNP mRNA that was abolished by GF109203X. Immunoreactive CNP was markedly increased in SMCs receiving 10% serum, 20 ng/ml PDGF-BB, or PMA, and was decreased in PDGF-treated and PMA-treated cells by AG 1296 and GF109203X, respectively. This report suggests that in humans, PDGF and other factors signaling through receptor tyrosine kinases and downstream activation of PKC could represent an important control for CNP expression in vascular smooth muscle.
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PMID:Increase of C-type natriuretic peptide expression by serum and platelet-derived growth factor-BB in human aortic smooth muscle cells is dependent on protein kinase C activation. 1677 70

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