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)

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.
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PMID:Down-regulation of protein kinase C potentiates atrial natriuretic peptide-stimulated cGMP accumulation in vascular smooth-muscle cells. 136 57

cGMP and Ca2+ are intracellular messengers in vertebrate rod photoreceptors. cGMP is the excitatory messenger, while intracellular free Ca2+ has been implied to be (one of) the messenger(s) in the process of light adaptation in vertebrate rod photoreceptors. The enzyme guanylyl cyclase (GC, EC 4.6.1.2.) catalyzes the reaction GTP-->cGMP + PPi. Bovine retinal rod outer segments (ROS) contain a particulate GC which is inhibited by an increase in free Ca2+ in the submicromolar range, although the precise molecular mechanism underlying this inhibition is unclear. We have developed an optical enzyme-coupled assay to study regulation of the particulate GC endogenous to bovine ROS. The particulate GC exhibited a Ca(2+)-inhibited (IC50 83-144 nM) activity of 13-23 nmol of PPi/(min-(mg of rhodopsin)). ATP increased the maximal velocity of GC by about 2-fold, and this increase was inhibited by the specific PKC inhibitors chelerythrine and the pseudosubstrate-based peptide inhibitor PKC R10-31N. When the factor that mediated the ATP-dependent increase in GC rate was removed by washing, the ATP-dependent increase in GC rate could be reestablished by addition of purified, constitutively active PKC.
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PMID:Activation by PKC of the Ca(2+)-sensitive guanylyl cyclase in bovine retinal rod outer segments measured with an optical assay. 771 73

Stimulation of guanylyl cyclase A (GC-A) by atrial natriuretic peptide (ANP) is antagonized by activators of protein kinase C (PKC). Thus, it has been suggested that PKC phosphorylates and desensitizes GC-A. Here, we have developed stable GC-A transfectants of NIH3T3 cells, which display marked reductions in hormone-dependent cGMP elevations and guanylyl cyclase activity after incubation with ANP or phorbol 12-myristate 13-acetate (PMA). ANP binding and immunoblot analysis indicated that the decreases were not due to receptor internalization or degradation. GC-A isolated from 32PO4-labeled cells contained phosphoserine and phosphothreonine. ANP and/or PMA addition caused substantial decreases in the 32P content of the receptor that coincided with reductions in hormone-dependent guanylyl cyclase activity. The specific PKC inhibitor, GF-109203X, completely blocked the PMA-dependent dephosphorylation and desensitization of GC-A but failed to inhibit either ANP-dependent process. Tryptic phosphopeptide maps of GC-A isolated from ANP- or PMA-treated cells were unique, suggesting that the sites that dephosphorylated in response to each agent were different. In contrast to previous reports, we conclude that PMA and ANP desensitization of GC-A are distinct events mediated by dephosphorylation of specific residues through PKC-dependent and -independent pathways, respectively.
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PMID:Protein kinase C-dependent desensitization of the atrial natriuretic peptide receptor is mediated by dephosphorylation. 791 Jan 66

We studied the activation and inactivation of recombinant guanylyl cyclase (GC) C stably expressed in human kidney 293 cells. Activation of GC-C by heat-stable enterotoxin (STa), Cd2+, hemin, or the detergent Triton X-100 was followed by a rapid inactivation of the enzyme. Adenine nucleotides were found to prevent the inactivation process in native membranes, as well as following enzyme solubilization and immunopurification. Inactivation of GC-C was not associated with dephosphorylation. However, the phosphorylation of GC-C was promoted by phorbol esters, known activators of protein kinase C. The activation of purified GC-C by STa required the presence of a nonspecific factor as exemplified by bovine serum albumin. When immunopurified GC-C, stabilized by ATP and bovine serum albumin, was analyzed by SDS-polyacrylamide gel electrophoresis under nonreducing conditions, proteins with almost twice the molecular mass (220 and 245 kDa) of the monomer were observed. The mobility of these high M(r) GC-C forms was reduced by STa, suggesting that STa induces a conformation change in a preexisting GC-C dimer. These results indicate that ATP interacts directly with GC-C, stabilizing its active conformation and that the activation of GC-C may occur in the absence of other specific regulatory factors.
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PMID:Heat-stable enterotoxin activation of immunopurified guanylyl cyclase C. Modulation by adenine nucleotides. 810 20

1. Kinins exert a contractile effect on rabbit aortic rings via the stimulation of B1 receptors. Des-Arg9-bradykinin (BK) is more potent than BK on this receptor type. The mode of action of des-Arg9-BK on rabbit aortic tissue has been studied by both the aortic ring contractility assay and a cellular model using cultured aortic smooth muscle cells (SMCs). 2. The des-Arg9-BK-induced contractions in rabbit aortic rings were unaffected by pretreatments with nifedipine, indomethacin, REV-5901 (a 5-lipoxygenase blocker) and LY-83583 (a guanylyl cyclase inhibitor); however, the protein kinase inhibitors H-7 and H-9 significantly reduced the maximal effect of des-Arg9-BK. 3. The contractile responses to des-Arg9-BK in calcium-free Krebs solution were slightly but not significantly attenuated in amplitude, as compared to paired control tissues bathed in Krebs solution, and sustained plateaus of contraction were observed in the absence of Ca2+. However, Ca2+ replenishment further increased the kinin-induced contraction measured in Ca(2+)-free bathing fluid. 4. Despite the lack of evidence of a mediating role for prostaglandin in the mechanical response to des-Arg9-BK, the kinin stimulated the release of prostacyclin from rabbit aorta rings measured as immunoreactive 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). 5. Smooth muscle cells (SMCs) derived from the rabbit aorta exhibit functional responses to des-Arg9-BK in acute release of 6-keto-PGF1alpha and of inositol phosphate turnover which were inhibited by pretreatment with the B1 receptor antagonist, Lys[Leu8]des-Arg9-BK, but not by the B2 receptor antagonist, Hoe-140. Preincubation of the cells with interleukin- 1 (IL-1) 20 h before stimulation with the kinin had no effect on basal inositol phosphate turnover, but potentiated the acute effect of des-Arg9-BK.6. These results suggest that second mesengers derived from the action of phospholipase C are produced by SMCs when B1 receptors are activated in rabbit aortic tissue. Intracellular calcium stores are primarily mobilized by des-Arg9-BK, although receptor-controlled calcium influx has not been ruled out, and may contribute to initiate the contractile responses. The maintenance of the contractile state involves protein kinase C activity and is consistent with a current model of SMC function. The cell model retains some of the cardinal properties of B1 receptor-mediated vascular responses: endothelium independent PGI2 release and up-regulation by the cytokine IL-1. PGI2 is not involved in the mechanical response, possible because the rabbit aorta is refractory to this prostaglandin.
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PMID:Vascular mode of action of kinin B1 receptors and development of a cellular model for the investigation of these receptors. 810 48

A decrease of cytoplasmic Ca(2+)-concentration in vertebrate photoreceptor cells after illumination is necessary for light adaptation. Although the mechanisms of adaptation is not completely understood, several Ca(2+)-dependent cellular processes have been discovered. Some involve calcium-binding proteins like recoverin, guanylyl cyclase-activating protein and calmodulin, and their target proteins rhodopsin kinase, guanylyl cyclase, the cGMP-gated channel, and NO synthase. The activity of several enzymes or channels is directly controlled by Ca2+ and does not involve calcium-binding proteins. These proteins are pyrophosphatase, protein kinase C and the cGMP-gated channel.
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PMID:Control of photoreceptor proteins by Ca2+. 855 70

Parafollicular (PF) cells secrete 5-hydroxytryptamine in response to increased extracellular Ca2+ ([Ca2+]e). This stimulus causes Cl- channels in PF secretory vesicles to open, leading to vesicle acidification. PF cells express a plasmalemmal heptahelical receptor (CaR) that binds Ca2+, Gd3+, and Ba2+. We now report that the CaR mediates vesicle acidification. Ca2+, Gd3+, and Ba2+ induced vesicle acidification, which was independent of channel-mediated Ca2+ entry. Agonist-induced vesicle acidification was blocked by pertussis toxin, inhibitors of phosphatidylinositol-phospholipase C, calmodulin, NO synthase, guanylyl cyclase, or protein kinase G. PF cells contained NO synthase immunoreactivity, and vesicles were acidified by NO donors and dibutyryl cGMP. [Ca2+]e, and Gd3+ mobilized thapsigargin-sensitive internal Ca2+ stores. [35S]G alpha i and [35S]G alpha q were immunoprecipitated from PF membranes incubated with agonists in the presence of [35S]adenosine 5'-O-(thiotriphosphate). Labeling of G alpha i but not G alpha q was antagonized by pertussis toxin. Vesicles acidified in response to activation of protein kinase C; however, protein kinase C inhibition blocked calcium channel- but not CaR-dependent acidification. We propose the following signal transduction pathway: CaR -> Gi -> phosphatidylinositol-phospholipase C -> inositol 1,4,5-trisphosphate -> [Ca2+]i -> Ca2+/calmodulin -> NO synthase -> NO -> guanylyl cyclase -> cGMP -> protein kinase G -> opens vesicular Cl- channel.
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PMID:Acidification of serotonin-containing secretory vesicles induced by a plasma membrane calcium receptor. 862 45

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

To characterize Ser1029 in STaR at a consensus sequence of phosphorylation site by PKC, two mutants of mS1029A with replacement of Ser1029 to Ala1029 and C delta 1029 lacking 22 amino acids including Ser1029 were prepared. Preincubation of the wild type-STaR (wt-STaR) transfectant with 1 microM PMA caused additional STa-mediated guanylyl cyclase (GC) activation compared to control, whereas the mS1029A- and C delta 1029-transfected cells did not show a similar enhanced GC activation by PMA. After metabolic labeling with [32P]phosphate, transfected cells with wt-STaR and mutants were incubated with 1 microM PMA. Subsequent 32P-radiolabeled proteins were immunoprecipitated using anti-STaR antibody, and analyzed by autoradiography after separation on SDS-PAGE. The immunoprecipitated wt-STaR but not mS1029A and C delta 1029 had a significant radioactivity. These results suggest that the effect of PMA on wt-STaR transfectants may be caused by phosphorylation of Ser1029. The C delta 1012 mutant, with further truncation (Gln1012-Phe1050) of the carboxy terminus, did not show STa-mediated GC activation. Based on these data, these 17 amino acids (Gln1012-Ala1028), essential for signaling of GC activation by STa, have an abundance of basic amino acids which might be functionally influenced by phosphorylation of Ser1029.
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PMID:The significance of Ser1029 of the heat-stable enterotoxin receptor (STaR): relation of STa-mediated guanylyl cyclase activation and signaling by phorbol myristate acetate. 879 7

We investigated the signaling pathways modulating histamine- and prostaglandin F2 alpha (PGF2 alpha)-induced contractions of human chorionic vasculature. Neomycin, a phospholipase C (PLC) inhibitor, attenuated PGF2 alpha and histamine contractile responses 40 and 60%, respectively. AIF4-, a G protein stimulant, induced a strong contraction alone but blocked histamine- and PGF2 alpha-induced contractions. Staurosporine (100 nM), a protein kinase C (PKC) inhibitor, attenuated the PGF2 alpha-dependent contractions by 50% but did not affect the histamine response. However, higher nonspecific inhibitory concentrations of staurosporine (1-2 microM) abolished histamine and PGF2 alpha contractile responses, presumably by inhibiting other protein kinases. Although, the PKC phorbol 12-myristate 13-acetate (PMA) did not affect basal tension or PGF2 alpha-dependent contractions, the histamine response was attenuated by 30%. Sodium nitroprusside (SNP), a guanylyl cyclase stimulant, strongly attenuated histamine- and PGF2 alpha-induced contractions. Tension increases were similarly attenuated by forskolin and isobutylmethylxanthine (IBMX), which increase intracellular cyclic AMP. In vessel rings prelabeled with [3H]myoinositol, PGF2 alpha and histamine increased [3H]inositol phosphate (IP) production 400 and 100%, respectively, indicating that PLC is stimulated by both agonists. Neomycin inhibited histamine- and PGF2 alpha-induced increases in [3H]IP production 60 and 40%, respectively. Staurosporine (0.1-1 microM) and PMA did not affect histamine- or PGF2 alpha-stimulated IP production. AIF4-alone increased IP production but blocked histamine- and PGF(2 alpha)-dependent IP increases. These observations suggest that at least part of the contractile responses due to PGF2 alpha and histamine are associated with stimulation of PLC through an AIF4(-)-sensitive G protein. The role of PKC is variable, because PGF2 alpha but not histamine tension responses were attenuated by PKC inhibition. In addition, therapeutic agents that increase cyclic AMP and cyclic GMP attenuated histamine- and PGF2 alpha-induced contractions in human chorionic vasculature, although histamine responses were relatively more sensitive to these agents.
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PMID:Mechanisms of prostaglandin F2 alpha and histamine-induced contractions in human chorionic vasculature. 887 81


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