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)

Cell proliferation and the expression of the protooncogenes c-fos and c-jun have been examined in the primary cultures of oligodendroglial (OL) progenitor cells in response to phorbol 12-myristate 13-acetate (PMA), serum, insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). Combined [3H]thymidine autoradiography and immunocytochemistry was used to assess the mitogenic response of O4 (an oligodendrocyte-specific marker)-positive OL progenitors. In addition, the rate of DNA synthesis was measured by the incorporation of [3H]thymidine into acid-precipitable material. It was found that all of the agents tested stimulated DNA synthesis in OL progenitors and induced a rapid increase in c-fos and c-jun protooncogene expression. The induction of c-fos gene expression and DNA synthesis in response to PMA was completely blocked by 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7), a potent inhibitor of protein kinase C (PKC), thereby suggesting a role for PKC in the control of c-fos expression and cell proliferation in OL progenitors.
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PMID:Cell proliferation and protooncogene induction in oligodendroglial progenitors. 143 84

Protein kinase C inhibitor was injected intracellularly by iontophoresis into CA1 somata either before or after long-term potentiation in the hippocampal slice preparation. Two different protein kinase C inhibitors, polymyxin B (PMXB) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), injected 10 min before long-term potentiation induction caused potentiated responses to return to baseline 15-35 min after induction without significantly affecting the initial magnitude of potentiation. There was no effect on long-term potentiation persistence when H-7 or PMXB was injected intracellularly 5 min after long-term potentiation induction. In contrast, focal extracellular micro-pressure ejection of protein kinase C inhibitor in the stratum radiatum, 15 or 30 min, but not 60 min after long-term potentiation induction caused decay of long-term potentiation to baseline. This is probably a presynaptic action since intracellular inhibitors injected postsynaptically were ineffective 5 min after long-term potentiation induction. Focal application to stratum pyramidale produced a weaker decay than to stratum radiatum suggesting a Schaffer collateral presynaptic terminal site of action. We propose that activation of postsynaptic protein kinase C activity is necessary for long-term potentiation persistence but this activity persists for less than 5 min after induction. Presynaptic protein kinase C activity is also necessary for persistence and is time-limited to less than 60 min. It is attractive to think that these two events are sequentially activated and employ different protein kinase C subtypes differentially localized to presynaptic or postsynaptic elements.
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PMID:Postsynaptic then presynaptic protein kinase C activity may be necessary for long-term potentiation. 143 83

The contractile effects of phorbol 12,13-dibutyrate (PDBu) on rabbit urinary bladder dome and urethra were investigated using muscle bath techniques. PDBu caused concentration-dependent contractions in both tissues, and these responses were not affected by pretreatment with atropine, phentolamine, hexamethonium or indomethacin. In both tissues, 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7), a potent inhibitor of protein kinase C (PKC), inhibited PDBu-induced contractions in a concentration-dependent manner. The maximum PDBu-induced contractions in bladder dome and urethra were 33.5 +/- 3.4 and 33.3 +/- 4.1% of KCl-induced maximum contractions, respectively. In Ca(2+)-free solution or after pretreatment with nifedipine (10(-6) M), PDBu-induced contractions were reduced but not completely abolished. Although pretreatment with PDBu (10(-8) M) did not have a significant effect on the contractile responses induced by carbachol (in bladder dome) and phenylephrine (in urethra), pretreatment with H-7 (100 microM) had an inhibitory effect on carbachol- and phenylephrine-induced contractions; tonic phase contractions were more sensitive than phasic contractions. These results indicate that PDBu has significant contractile effects in rabbit bladder dome and urethra, and that the effects may be partly mediated by activation of PKC. PKC activation might also contribute to agonist-induced contractile responses in these tissues.
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PMID:Effects of phorbol ester on lower urinary tract smooth muscles in rabbits. 145 33

Catecholamines have been shown to activate hypothalamic corticotropin-releasing factor-41 (CRF) synthesis and release. In order to study the mechanisms involved, fetal hypothalamic cells were cultured and CRF release was measured by radioimmunoassay. Norepinephrine (NE) induced CRF release in a dose-dependent manner. Further studies were performed with a protein kinase C inhibitor, H-7(1-(5-isoquinolinesulfonyl)-2-methylpiperazine) and a protein kinase A inhibitor, IP-20. NE-stimulated CRF release was reduced by H-7 (5 and 50 microM) in a dose-dependent fashion, while 5 microM IP-20 resulted in a small but significant inhibition. Pretreatment of the cells for 15 h with 20 and 200 nM 12-O-tetradecanoylphorbol-13-acetate, which down-regulates protein kinase C activity, blocked the release of CRF in response to NE (1 microM), further supporting protein kinase C as a mediator for NE-activated CRF release. Pretreatment with 50 and 500 ng/ml pertussis toxin (15 h) resulted in a dose-dependent inhibition of NE-activated CRF release. Both dexamethasone and aldosterone at the concentrations of 1 microM reduced NE-induced CRF release. These results suggest that CRF can be released from hypothalamic neurons in response to NE through both protein kinase C- and protein kinase A-dependent mechanisms, and that pertussis toxin-sensitive G-proteins are also involved in this response. Furthermore, glucocorticoids and mineralocorticoids can reduce NE-activated CRF release from cultured hypothalamic cells.
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PMID:Mechanisms of norepinephrine mediated corticotropin-releasing factor-41 release from cultured fetal hypothalamic cells. 148 3

The effects of arachidonic acid (AA) and other long-chain fatty acids on voltage-dependent Ca channel current (ICa) were investigated, with the whole cell patch clamp method, in longitudinal smooth muscle cells of rabbit ileum. 10-30 microM AA caused a gradual depression of ICa. The inhibitory effect of AA was not prevented by indomethacin (10 microM) (an inhibitor of cyclooxygenase) or nordihydroguaiaretic acid (10 microM) (an inhibitor of lipoxygenase). 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine (H7; 25-50 microM) or staurosporine (2 microM) (inhibitors of protein kinase C) did not block the AA-induced inhibition of ICa, and application of phorbol ester (a protein kinase C activator) (phorbol-12,13-dibutyrate, 0.2 microM) did not mimic the AA action. Some other cis-unsaturated fatty acids (palmitoleic, linoleic, and oleic acids) were also found to depress ICa, while a trans-unsaturated fatty acid (linolelaidic acid) and saturated fatty acids (capric, lauric, myristic, and palmitic acids) had no inhibitory effects on ICa. Myristic acid consistently increased the amplitude of ICa at negative membrane potentials. The present results suggest the possible role of AA, and perhaps other fatty acids, in the physiological and/or pathological modulation of ICa in smooth muscle.
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PMID:Modulation of voltage-dependent Ca channel current by arachidonic acid and other long-chain fatty acids in rabbit intestinal smooth muscle. 151 58

The protein kinase inhibitor 1-(5'-isoquinolinesulfonyl)-2-methylpiperazine (H7) has been widely used because of its ability to inhibit cyclic AMP- and cyclic GMP-dependent protein kinases (PKA and PKG) and protein kinase C (PKC) at roughly equal concentrations; it is much less potent on other kinases. Previous studies in other laboratories have found that H7 samples from different commercial sources have different properties in cellular studies and protein kinase C inhibition assays. We now report the results of chemical and biological tests which show that H7 samples also differ in chemical structure, again depending on their commercial source. Chemical synthesis and NMR spectroscopy indicate that H7 from most suppliers has the structure originally proposed for H7, while "H7" from another supplier is in fact its 3-methylpiperazine positional isomer.
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PMID:The structure and biological activities of the widely used protein kinase inhibitor, H7, differ depending on the commercial source. 153 Jun 23

Exposure of human polymorphonuclear neutrophils to phorbol 12-myristate 13-acetate (PMA) results in a 70-75% reduction in the specific binding of 125I-granulocyte-macrophage colony-stimulating factor (GM-CSF) to its receptors. The PMA-induced reduction in 125I-GM-CSF binding is due to a decrease in the number of available GM-CSF receptors, as derived from Scatchard analysis of the binding data. On the other hand, the phorbol ester 4-alpha-phorbol 12,13-didecanoate (4 alpha-PDD) fails to affect 125I-GM-CSF binding. PMA promotes phosphorylation on tyrosine residues of several proteins, as demonstrated by Western blotting analysis using antiphosphotyrosine antibodies. The molecular masses of those proteins are 41, 55, 66, 78, 85, 104, and 115 kDa. GM-CSF increases the levels of the tyrosine phosphorylation of several proteins, the majority of which have similar Mr to those found in PMA-stimulated neutrophils. This increase, on all but the 41-kDa protein, is partially prevented by treatment of the cells with PMA. The inhibition by PMA of GM-CSF binding to its receptors and its phosphorylated effects is partially prevented by the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine and, to a greater extent, by staurosporine. It is suggested that PMA, through the activation of protein kinase C, interrupts the excitation-response sequence initiated by GM-CSF, which includes tyrosine phosphorylation, and that the earliest altered step is the binding of GM-CSF to its receptor.
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PMID:Phorbol ester inhibits granulocyte-macrophage colony-stimulating factor binding and tyrosine phosphorylation. 153 18

The transmucosal fluxes of Na+ and Cl- were studied in Giardia lamblia infected mice in the presence or absence of phorbol-12-myristate-13-acetate (PMA), the activator of protein kinase C (PKC) or 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine (H-7), the inhibitor of PKC or Ca(2+)-calmodulin. There was net secretion of Na+ and Cl- in infected animals, while in control animals there was net absorption of these ions. The addition of ionophore or PMA resulted in net secretion of Na+ and Cl- in the control group while in the infected group there was no change in the fluxes of these ions. The selective potent inhibitor of protein kinase C, H-7, reversed the secretion of Na+ and Cl- in infected group to absorption. The addition of PMA and Ca(2+)-ionophore together in the infected group had a partial additive effect. This study suggests that G. lamblia induced fluid secretion involves protein kinase C and further protein kinase C acts in synergism with calcium.
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PMID:Study on the mechanism of Giardia lamblia induced diarrhoea in mice. 154 Jun 58

We searched for a possible role for protein kinase C in the growth of human erythroid progenitor cells, using pharmacologic approaches. Two protein kinase C inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) and staurosporine, dose-dependently inhibited the growth of immature erythroid progenitor cells (BFU-E) induced by interleukin 3 (IL-3) plus erythropoietin (Ep) or granulocyte macrophage colony-stimulating factor (GM-CSF) plus Ep whereas a weaker analog of H-7, N-(2-guanidinoethyl)-5-isoquinoline sulfonamide (HA-1004), had no effect on the number of BFU-E. These three compounds had no effect on the growth of mature erythroid progenitor cells (CFU-E) stimulated by Ep. The culture of accessory cell-depleted bone marrow demonstrated that the effects of these compounds on colony formation do not appear to be mediated by accessory cells. The potential of these compounds to inhibit the GM-CSF-dependent growth of KG-1 cells correlated well with the extent of their inhibitor of protein kinase C activities from KG-1 cells. Thus, the protein kinase C system is apparently involved in the growth of BFU-E, supported by IL-3 or GM-CSF. The growth signal for CFU-E transduced by Ep may be achieved through other systems.
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PMID:A role for protein kinase C in the growth of human erythroid progenitor cells. 154 67

A single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin caused an induction of epidermal ornithine decarboxylase (ODC) activity. When mice were topically pretreated with staurosporine, a most potent protein kinase C inhibitor, 6-84 h prior to TPA treatment, TPA-caused ODC induction was markedly enhanced. The enhancement of TPA-caused ODC induction by staurosporine was most pronounced when the time interval between staurosporine and TPA treatment was 36 h. Staurosporine elicited this enhancing effect in a dose-related manner. Staurosporine by itself also induced epidermal ODC activity. But the activity induced was very slight and would not directly contribute to the enhancing effect of this compound. Although staurosporine markedly augmented TPA-caused ODC induction, staurosporine-caused ODC induction was not augmented by this compound. Other protein kinase C inhibitors, such as 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, sphingosine and palmitoylcarnitine did not mimic the enhancing effect of staurosporine. These results indicate that the enhancement of ODC induction by staurosporine is specific for the induction caused by TPA and that this enhancing effect is not related to the protein kinase C inhibitory action of staurosporine. TPA-caused epidermal ODC induction was inhibited by indomethacin, and this inhibition was reversed by prostaglandin E2 (PGE2). Staurosporine-caused ODC induction was also inhibited by indomethacin but the inhibition was not reversed by PGE2, indicating that the mechanism of staurosporine-caused ODC induction is different from that of TPA.
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PMID:Staurosporine, a potent protein kinase C inhibitor, augments phorbol ester-caused ornithine decarboxylase induction in mouse epidermis. 154 24


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