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. Mouse atria were incubated with [3H]-noradrenaline, and the outflow of radioactivity due to electrical field stimulation (5 Hz, 60 s) was used as an index of noradrenaline release. Angiotensin II (0.01 and 0.1 microM) significantly enhanced the stimulation-induced (S-I) outflow of radioactivity. 2. Phorbol 12-myristate 13-acetate (0.001, 0.03, 0.1 and 1.0 microM), a protein kinase C activating phorbol ester, significantly enhanced the S-I outflow of radioactivity. When angiotensin II (0.1 microM) was present with the concentration of phorbol 12-myristate 13-acetate that was maximally effective in increasing the S-I outflow (0.1 microM), the enhancement of S-I outflow produced by angiotensin II was maintained. 3. Polymyxin B (70 microM), an inhibitor of protein kinase C, significantly inhibited the S-I outflow. Polymyxin B also inhibited the enhancement of the S-I outflow produced by angiotensin II (0.1 microM). 4. In another series of experiments mice were injected with pertussis toxin (1.5 micrograms per mouse), 4 days before their atria were removed. The effectiveness of pertussis toxin pretreatment was determined indirectly using carbachol. Carbachol caused a concentration-dependent fall in both the rate and force of beating of isolated spontaneously beating atria from mice pretreated with vehicle. This effect of carbachol was not seen with atria from mice pretreated with pertussis toxin. 5. Pertussis toxin pretreatment did not alter the enhancement of the S-I outflow of radioactivity produced by angiotensin II (0.01 and 0.1 microM). 6. These results suggest that angiotensin II receptor modulation of noradrenaline release is not mediated through either a pertussis toxin sensitive guanine nucleotide-binding protein or activation of protein kinase C.
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PMID:Effect of phorbol ester and pertussis toxin on the enhancement of noradrenaline release by angiotensin II in mouse atria. 272 Feb 95

We studied a nine-year-old boy with severe, recurrent infections. The patient was exposed in utero to azathioprine and prednisone. He had autoimmune hemolytic anemia, bronchiectasis, and Hodgkin's disease. The patient's circulating lymphocytes were normal in number and phenotype, but stimulation of the T-cell receptor by antigens, mitogens, and monoclonal antibodies failed to induce interleukin-2-receptor expression, interleukin-2 synthesis, or lymphocyte proliferation. The early biochemical events necessary to initiate lymphocyte activation--accumulation of the second messenger diacylglycerol, activation of the enzyme protein kinase C, and elevation of the free intracellular calcium concentration--failed to occur in this patient's lymphocytes. The defect in the lymphocyte could be corrected in vitro by two agents that bypass the receptor-mediated signal mechanism (the diacylglycerol analogue phorbol and the calcium ionophore ionomycin). Further studies localized the defect in signal transduction to the interaction between cell-surface receptors and the guanine nucleotide-binding protein. We conclude that this patient's immunodeficiency was caused by a defective coupling of surface receptors to signal-transducing proteins in his T lymphocytes, resulting in failure of lymphocyte activation.
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PMID:An immunodeficiency characterized by defective signal transduction in T lymphocytes. 278 45

This review seeks to assemble recent discoveries about insulin receptor/kinase, guanine nucleotide-binding proteins, phosphatidyl inositol metabolism, and protein phosphatases to provide a mechanistic pathway by which insulin would alter carbohydrate and fat metabolism. It proposes a hypothetical chain of events that leads from the insulin receptor to protein phosphatase-1. The sequence starts with insulin binding to its receptor, activating the intrinsic receptor/kinase activity. The insulin receptor phosphorylates a guanine nucleotide-binding protein, which activates a particular phospholipase C. This in turn stimulates the production of two lipid-derived messengers: inositol-phospho-glucosamine and diacylglycerol. These messengers trigger the effects of insulin. The diacylglycerol produced by insulin is thought to be analogous to the diacylglycerol produced by alpha-adrenergic stimulation, which activates protein kinase C. Activation of this kinase could account for increases in phosphorylation of certain proteins. The inositol-phospho-glucosamine is the cytosolic messenger for insulin. One of the enzymes activated by insulin is protein phosphatase type-1. It is known that the phosphatase decreases phosphorylation of certain target enzymes. In response to insulin, activation of protein phosphatase type-1 occurs with a stable conformational change that may involve rearrangement of disulfide bonds. Rearrangement is either directly in response to the cytosolic messenger or is catalyzed by an isomerase activated by the insulin messenger. Ultimately, protein phosphatase type-1 and/or the disulfide isomerase may together mediate the pleiotropic effects of insulin on carbohydrate and fat metabolism.
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PMID:Proposal for a pathway to mediate the metabolic effects of insulin. 283 73

To clarify the role of the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) in GH secretion in human somatotrophs and the effects of inhibitors of GH secretion on this mechanism, we studied the effects of 12-tetradecanoylphorbol-13-acetate (TPA) and phospholipase C (Plase C) on GH secretion and the interactions of somatostatin (SRIH), bromocriptine, and pertussis toxin (IAP) with TPA or Plase C, using human GH-secreting pituitary adenoma cells in culture. SRIH (10(-9)-10(-7) M) inhibited and TPA (10(-10)-10(-8) M) and Plase C (0.125-1.0 U/mL) stimulated GH secretion. SRIH (10(-9)-10(-7) M) inhibited GH release induced by TPA (10(-8) M) or Plase C (1.0 U/mL). Bromocriptine (10(-8) M) also inhibited 10(-8) M TPA-induced GH secretion. When adenoma cells were treated with 100 ng/mL IAP for 24 h, basal and TPA-induced GH secretion rates did not change. However, the inhibitory effects of SRIH (10(-8) M) or bromocriptine (10(-8) M) on basal and 10(-8) M TPA-stimulated GH secretion were attenuated. In addition, IAP reduced GH secretion induced by 0.5 U/mL Plase C, while SRIH inhibition of Plase C-evoked GH release was diminished by IAP. We conclude that the hydrolysis of PIP2 by Plase C, which causes activation of protein kinase C by 1,2-diacylglycerol and Ca2+ mobilization by inositol 1,4,5-triphosphate, is a physiological intracellular mechanism leading to GH secretion in human somatotrophs; SRIH inhibits GH secretion mediated by this mechanism, and bromocriptine blocks at least protein kinase C-mediated GH release; the inhibitory guanine nucleotide-binding protein (Ni) is involved in these inhibitory effects of SRIH and bromocriptine; and Ni modulates the breakdown of PIP2 by Plase C.
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PMID:Phorbol ester and phospholipase C-induced growth hormone secretion from pituitary somatotroph adenoma cells in culture: effects of somatostatin, bromocriptine, and pertussis toxin. 288 Aug 63

To examine the potential mechanisms by which somatostatin inhibits gastric acid secretion we studied its effects on isolated canine gastric parietal cells. Using 125I-[Leu8-D-Trp22-Tyr25]somatostatin-28 as ligand, we identified somatostatin-binding sites in parietal cell-enriched fractions of fundic mucosa. Two binding sites with respective dissociation constants of 3.2 X 10(-9) and 2.1 X 10(-7) M were identified. Somatostatin-14 and -28 were equally potent both in displacing bound ligand and in inhibiting parietal cell activity as measured by [14C]aminopyrine uptake. Pertussis toxin reversed the ability of somatostatin to inhibit the uptake of [14C]aminopyrine and production of cAMP by parietal cells stimulated with histamine and forskolin but not with dibutyryl cAMP or pentagastrin. Furthermore, somatostatin had no effect on parietal cell membrane inositol phospholipid turnover or changes in protein kinase C (Ca2+/phospholipid-dependent enzyme) activity induced by carbachol or pentagastrin. These data indicate that somatostatin directly inhibits parietal cell activity via mechanisms both dependent on and independent of the pertussis toxin-sensitive inhibitory guanine nucleotide-binding protein.
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PMID:Mechanisms for direct inhibition of canine gastric parietal cells by somatostatin. 288 65

The effects of pretreatment of rabbit neutrophils with phorbol 12-myristate 13-acetate on the ability of pertussis toxin to catalyze ADP-ribosylation and of fMet-Leu-Phe to activate a high-affinity GTPase in these cell homogenates were examined. The addition of phorbol 12-myristate 13-acetate, but not 4 alpha-phorbol 12,13-didecanoate, to intact cells was found to stimulate by more than 100% the pertussis toxin-dependent ribosylation of a 41 kDa protein (either the alpha-subunit of the 'inhibitory' guanine nucleotide-binding protein N or a closely analogous protein) and to inhibit by more than 60% the activation by fMet-Leu-Phe of the GTPase of the neutrophil homogenates. The addition of fMet-Leu-Phe to intact cells increases the ADP-ribosylation catalyzed by pertussis toxin of the 41 kDa protein. On the other hand, the exposure of neutrophil homogenates to fMet-Leu-Phe results in a decreased level of ADP-ribosylation. This decreased ribosylation reflects a dissociation of the GTP-binding protein oligomer that is not followed by association, possibly because of the release of the alpha-subunit into the suspending media. The implications of these results for the understanding of the mechanism of inhibition of cell responsiveness by phorbol esters and the heterologous desensitization phenomenon are discussed. Prominent among these are the possibilities that (i) the rate of dissociation of the Ni oligomer is affected by the degree of its phosphorylation by protein kinase C, and/or (ii) the dissociated phosphorylated alpha-subunit (the 41 kDa protein) is functionally less active than its dephosphorylated couterpart.
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PMID:Treatment of rabbit neutrophils with phorbol esters results in increased ADP-ribosylation catalyzed by pertussis toxin and inhibition of the GTPase stimulated by fMet-Leu-Phe. 300 12

In the chain of events by which chemotactic peptides stimulate NADPH oxidase-catalyzed superoxide formation in human neutrophils, the involvements of a pertussis toxin-sensitive guanine nucleotide-binding protein (N-protein), mobilization of intracellular calcium and protein kinase C stimulation have been proposed. Superoxide formation was studied in membranes from human neutrophils; NADPH oxidase was stimulated by arachidonic acid in the presence of neutrophil cytosol. Fluoride and stable GTP analogues, such as GTP gamma S and GppNHp, which all activate N-proteins, enhanced NADPH oxidase activity up to 4-fold. GDP beta S inhibited the effect of GTP gamma S. These data suggest that NADPH oxidase is regulated by an N-protein, independent of an elevation of the cytoplasmic calcium concentration.
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PMID:Guanine nucleotides stimulate NADPH oxidase in membranes of human neutrophils. 301 56

We have reported previously that in the vascular smooth muscle cell line A-10 (ATCC CRL 1476), vasopressin stimulated phosphatidylinositol turnover Ca2+ efflux and inhibited isoproterenol-stimulated cAMP accumulation. Here we report that pretreatment of these cells with phorbol dibutyrate, an activator of protein kinase C, attenuated the responses to vasopressin and isoproterenol. This effect was concentration dependent and could be observed after pretreatment for 2 min. 4 alpha Phorbol 12,13-didecanoate, which does not activate protein kinase C, did not attenuate the responses. These data suggest that activation of protein kinase C by phorbol dibutyrate attenuates the responses of vascular smooth muscle cells to isoproterenol and vasopressin. Although phorbol ester did not affect [3H]-8-arginine vasopressin binding to intact cells, it appeared to uncouple vasopressin receptors from guanine nucleotide-binding protein.
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PMID:Phorbol ester-mediated inhibition of vasopressin and beta-adrenergic responses in a vascular smooth muscle cell line. 302 29

We have localized a guanine nucleotide-binding protein, Go, in rat brain by immunohistochemistry with a selective polyclonal antiserum to the alpha 39 subunit of Go. Specific staining is widely distributed, abundant in neuropil, absent from neuronal cell bodies, and displays regional heterogeneity. Staining is enriched in cerebral cortex, particularly the molecular layer, neuropil of the hippocampal formation, striatum, substantia nigra pars reticulata, molecular layer of the cerebellum, substantia gelatinosa of the spinal cord, and posterior pituitary. High density staining in the substantia nigra reflects a Go-containing striatonigral pathway since striatal lesions reduce ipsilateral immunostaining in the pars reticulata. Confirming immunostaining, quantitative [32P]ADP-ribosylation of nigral membranes with pertussis toxin indicates a 66% +/- 11% (mean +/- SEM) reduction of Go ipsilateral to striatal lesions. Go may be associated with Purkinje cells in the cerebellum since membranes from mutant mice (Nervous), which postnatally lose Purkinje cells, are markedly depleted in pertussis toxin substrate. The localizations of Go correspond in many areas with those of protein kinase C, a component of the phosphatidylinositol cycle, suggesting a major role for Go in the brain related to regulation of the phosphatidylinositol cycle.
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PMID:Go, a guanine nucleotide-binding protein: immunohistochemical localization in rat brain resembles distribution of second messenger systems. 308 88

The GDP-bound alpha subunit of transducin, but not the guanosine 5'-[gamma-thio]triphosphate-bound one, undergoes phosphorylation on tyrosine residues by the insulin receptor kinase and on serine residues by protein kinase C. Holotransducin is poorly phosphorylated by the insulin receptor kinase and is not phosphorylated by protein kinase C. Neither holotransducin nor any of its subunits were phosphorylated by the cAMP-dependent protein kinase. That a given subunit of transducin undergoes multisite phosphorylation depending on the type of nucleotide bound to it or the nature of the kinase suggests that hormone-dependent phosphorylation could provide a versatile mode for regulation of guanine nucleotide-binding protein (G protein) function. In particular, the findings that certain G proteins serve as substrates for both the insulin receptor kinase and protein kinase C implicate G proteins in playing a key role in mediating the action of insulin and ligands that act to activate protein kinase C.
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PMID:Multisite phosphorylation of the alpha subunit of transducin by the insulin receptor kinase and protein kinase C. 309 81


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