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 distribution of calcium-activated, phospholipid-dependent protein kinase (protein kinase C) between cytosol and membrane fractions was analyzed in cultured pituitary gonadotrophs during treatment with gonadotropin-releasing hormone (GnRH). In pituitary cells purified by centrifugal elutriation, the extent of protein kinase C redistribution during GnRH stimulation was correlated with the enrichment of gonadotrophs. GnRH-stimulated release of luteinizing hormone (LH) from gonadotroph-enriched cells was accompanied by a rapid and dose-dependent decrease in cytosolic protein kinase C and by a corresponding increase in protein kinase C activity in the particulate fraction. Retinal directly inhibited the activity of cytosolic protein kinase C and also attenuated the release of LH from GnRH-stimulated gonadotrophs. These findings, and the ability of GnRH to cause rapid translocation of cytosolic protein kinase C to a membrane-associated form, suggest that hormonal activation of protein kinase C is an intermediate step in the stimulation of pituitary LH secretion by GnRH.
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PMID:Hormone-induced redistribution of calcium-activated phospholipid-dependent protein kinase in pituitary gonadotrophs. 315 33

The present study was designed to test the hypothesis that there is a functional interaction between the calcium-calmodulin system, which appears to mediate the action of gonadotropin-releasing hormone (GnRH), and activators of protein kinase C, which stimulate luteinizing hormone (LH) release by a mechanism which does not require extracellular calcium. We have examined a diacylglycerol and a phorbol ester, which both activate protein kinase C and stimulate LH release. These compounds show synergistic action with calcium ionophore A23187 as secretogogues. Pimozide (a calmodulin antagonist), methoxyverapamil (a calcium ion channel inhibitor), and Ac[D-pCl-Phe1,2-D-Trp3-D-Lys6-D-Ala10]GnRH (a potent gonadotropin-releasing hormone antagonist) were used to show that the diacylglycerol and phorbol ester can stimulate LH release in a manner that is independent of both Ca2+ and calmodulin and do not work by means of a direct action on the GnRH receptor. These observations, coupled with previously published reports that extracellular Ca2+ mobilization is both necessary and sufficient for initiation and perpetuation of GnRH-stimulated LH release, indicate that activation of protein kinase C by endogenous diacylglycerols may serve as an amplifier of the GnRH-stimulated signal which appears to be mediated independently by the Ca2+-calmodulin system.
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PMID:Diacylglycerols and protein kinase C. Potential amplifying mechanism for Ca2+-mediated gonadotropin-releasing hormone-stimulated luteinizing hormone release. 315 62

When cultured pituitary cells were stimulated with synthetic diacylglycerol such as 1-oleoyl-2-acetylglycerol (OAG), or with a potent tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which are known stimulators of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C), enhanced release of luteinizing hormone (LH) was observed. Similarly, LH release was also stimulated by the Ca2+-ionophore, A23187. Simultaneous presence of A23187 and OAG or TPA resulted in a synergistic response that mimicked the full physiological response to gonadotropin releasing hormone (GnRH). Removal of extracellular Ca2+ only slightly affected the stimulatory action of TPA and OAG on LH release, but completely blocked the effect of GnRH. The results suggest that the stimulatory effect of GnRH on LH release may be mediated by two intracellular pathways involving Ca2+ and diacylglycerol as second messengers.
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PMID:Synergistic stimulation of luteinizing hormone (LH) release by protein kinase C activators and Ca2+-ionophore. 316 5

The involvement of protein kinase C in the signal transduction of gonadotropin-releasing hormone (GnRH) action was investigated with a GnRH superagonist, partial agonists, and antagonists in intact rat pituitary cells. Exposure of 32P-labeled cells to GnRH or to the superagonist [D-Nal(2)6]GnRH (200 times GnRH potency in vivo) induced the enhanced phosphorylation of 42-, 34-, 11-, and 10-kDa proteins and the dephosphorylation of a 15-kDa protein as assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/autoradiography. This effect was blocked in a dose-dependent manner by potent GnRH antagonists. At its maximally effective concentration of 10(-9) M, [D-Nal(2)6]GnRH induced an up to 2 times more pronounced phosphorylation of endogenous substrates than GnRH at 10(-7) M. This was in accord with its ability to cause an 8-fold increase in the translocation of protein kinase C to the particulate fraction vs. 3.4-fold for GnRH. This effect correlated with potency for a series of GnRH agonists ( [D-Nal(2)6]GnRH greater than GnRH greater than [Gly2]LH-RH) and was prevented by GnRH antagonists, as assessed by a novel phorbol ester receptor binding assay and by a standard kinase assay. Downregulation of protein kinase C by prolonged incubation of the pituitary cells with high concentrations of active phorbol esters abolished protein kinase C activity and also prevented the phosphorylation induced by GnRH, or [D-Nal(2)6]GnRH. The same effect was obtained by preincubating the cells with the protein kinase C inhibitor H-7. In this study we identify for the first time physiological substrates for protein kinase C in intact pituitary cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphorylation substrates for protein kinase C in intact pituitary cells: characterization of a receptor-mediated event using novel gonadotropin-releasing hormone analogues. 331 25

To explore the mechanism of gonadotropin-releasing hormone (GnRH) action on Leydig cell steroidogenesis the effects of a GnRH analog (GnRHa) were compared to those of 12-O-tetradecanoylphorbol 13-acetate (TPA). Both compounds acutely stimulated androgen production 2-4 fold with EC50's of 9 nM (TPA) and 0.2 nM (GnRHa). The effects of TPA and GnRHa were not additive and neither compound acutely altered the luteinizing hormone (LH) concentration-response relationship. After 24 h of exposure to TPA or GnRHa the ability of LH to stimulate androgen production was impaired. The parallel effects of TPA and GnRHa on Leydig cell steroidogenesis suggest that they are acting via similar mechanisms; presumably the activation protein kinase C.
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PMID:Stimulation and inhibition of Leydig cell steroidogenesis by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate: similarity to the effects of gonadotropin-releasing hormone. 389 59

The present experiments were designed to evaluate the role of protein kinase C activation on the secretion of the neural peptide, LHRH, from hypothalamic nerve terminals in vitro. Two specific protein kinase C activators, diacylglycerol (1,2-didecanoylglycerol, DiC10) and a phorbol ester (12,13-dibutyrate, PDBu) were used as probes. In addition to LHRH, secretion of prostaglandin E2 (PGE2) was also measured, since previous studies from our laboratory indicate that this arachidonic acid metabolite is intimately involved in the LHRH secretory process. PDBu at a dose of 200 nM significantly enhanced LHRH secretion from median eminence nerve terminals; in addition, a more modest but significant stimulation of PGE2 release was also observed. DiC10 (100 microM), on the other hand, enhanced PGE2 release but had no clear effect on LHRH secretion. Release of LHRH, however, was clearly stimulated when the lipoxygenase inhibitor nordihydroguaiaretic acid was added to the medium, suggesting that some arachidonic acid metabolites are inhibitory to LHRH secretion. The results indicate that protein kinase C activation leads to an enhanced secretion of LHRH. In addition, they suggest that 1,2-diacylglycerol may also activate the formation of arachidonoyl residues inhibitory to LHRH release.
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PMID:Diacylglycerol and phorbol esters enhance LHRH and prostaglandin E2 secretion from median eminence nerve terminals in vitro. 391 Jan 72

In rat pituitary gonadotropes, gonadotropin-releasing hormone (GnRH) stimulates rhythmic release of Ca2+ from stores sensitive to inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], which in turn induces an oscillatory activation of apamin-sensitive Ca2+-activated K+ current, IK(Ca). Since GnRH also activates protein kinase C (PKC), we investigate the action of PKC while simultaneously measuring intracellular Ca2+ concentration ([Ca2+]i) and IK(Ca). Stimulation of PKC by application of phorbol 12-myristate 13-acetate (PMA) did not affect basal [Ca2+]i. However, PMA or phorbol 12,13-dibutyrate (PdBu), but not the inactive 4alpha-phorbol 12,13-didecanoate (4alpha-PDD), reduced the frequency of GnRH-induced [Ca2+]i oscillation and augmented the IK(Ca) induced by any given level of [Ca2+]i. The slowing of oscillations and the enhancement of IK(Ca) were mimicked by synthetic diacylglycerol (1,2-dioctanoyl-sn-glycerol) and could be induced during ongoing oscillations that had been initiated irreversibly in cells loaded with guanosine 5'-O-(3-thiotriphosphate) (GTP-[gammaS]). In contrast, when oscillations were initiated by loading cells with Ins(1,4,5)P3, phorbol esters enhanced IK(Ca) without affecting the frequency of oscillation. The protein kinase inhibitor, staurosporine, reduced IK(Ca) without affecting [Ca2+]i and partially reversed the phorbol-ester-induced slowing of oscillation. Therefore, activation of PKC has two rapid effects on gonadotropes. It slows [Ca2+]i oscillations probably by actions on phospholipase C, and it enhances IK(Ca) probably by a direct action on the channels.
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PMID:Modulation of Ca2+ oscillation and apamin-sensitive, Ca2+-activated K+ current in rat gonadotropes. 747 15

The LHRH receptor in alpha T3-1 gonadotrope cells was shown to bring about a marked and sustained activation of MAP kinase. This response was prevented by protein kinase C inhibition or down-regulation and could be partially mimicked by phorbol ester. Additional evidence for inhibition of this response by pertussis toxin and partial mimicry by mastoparan (in a pertussis toxin-sensitive manner) provides the first evidence for Gi/Go-mediated signal transduction by the LHRH receptor. This dual mechanism of MAP kinase activation appears to be exceptional amongst the G protein-linked receptors that have been investigated.
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PMID:Activation of MAP kinase by the LHRH receptor through a dual mechanism involving protein kinase C and a pertussis toxin-sensitive G protein. 748 30

Using a transgenic mouse derived GnRH expressing neuronal cell line, GT1-3, we studied the effects of activation of cAMP, Ca2+ and protein kinase C pathways by forskolin, ionomycin and the phorbol ester phorbol 12-myristate 13-acetate (PMA), respectively, upon gonadotropin-releasing hormone (GnRH) secretion, cellular peptide content, mRNA and RNA primary transcript levels. Forskolin, ionomycin and phorbol ester all caused an increase in GnRH secretion in GT1-3 cells in a time and dose-dependent manner during a short-term (1 h) static incubation. Prolonged treatment with forskolin (10 microM), ionomycin (1 microM) and PMA (10 nM) for 12 or 24 h resulted in significant decreases in GnRH mRNA levels. Time-course studies showed that the increases in GnRH secretion stimulated by forskolin, ionomycin and PMA were gradually attenuated over time in parallel with the decreases in mRNA expression. In contrast, there were only small and variable changes in the GnRH cellular content. Studies using a GnRH antagonist (100 microM) suggested that the released GnRH has a negative feedback effect on its own secretion. However, co-incubation with the GnRH antagonist did not alter the inhibitory effects on GnRH mRNA levels by the secretagogues. Further studies on the transcriptional effects of forskolin, ionomycin and PMA on GnRH gene expression in GT1-3 cells revealed that all three secretagogues suppressed GnRH RNA primary transcript levels, with forskolin having a slower time course of action. Thus, the inhibition of cytoplasmic GnRH mRNA, and presumably its synthesis, after 12-24 h of secretagogue treatment may be due at least in part to a suppression of GnRH gene transcription.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Second messenger regulation of mouse gonadotropin-releasing hormone gene expression in immortalized mouse hypothalamic GT1-3 cells. 752 6

In goldfish, growth hormone (GH) secretion is regulated by multiple neuroendocrine factors. Among these regulators, gonadotropin-releasing hormone (GnRH) and dopamine (DA) are effective stimulators of GH release. The stimulatory actions of GnRH and DA are mediated by GnRH and DA D1 receptors on somatotropes, respectively. In this article, results from recent in vitro pharmacological and electrophysiological studies examining the possible involvement of extracellular Ca2+, protein kinase C, voltage-sensitive Ca2+ channels (VSCC) and phospholipase A2 in mediating GnRH-induced GH release are presented. Results from experiments investigating the possible interactions of cyclic adenosine 3',5'-monophosphate (cAMP), and extracellular Ca2+ entry through VSCC in mediating the DA D1-elicited GH response are also reported. These data were discussed in conjunction with other information available in the literature on the signal transduction mechanisms mediating GH secretion in goldfish. Based on these findings, a model for the transduction pathways integrating the initiation and maintenance of the distinct GnRH-induced and DA D1-elicited GH responses was proposed. GnRH and DA stimulate GH release via separate PKC- and cAMP-dependent mechanisms, respectively. These signalling mechanisms appear to act on distinct GH pools. PKC and cAMP subsequently activate VSCC. Ca2+ entry through VSCC plays a role in the sustained GH release response by enhancing the PKC- and cAMP-induced GH release.
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PMID:Signal transduction pathways in GnRH- and dopamine D1-stimulated growth hormone secretion in the goldfish. 753 77


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