Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of protein kinase C (PKC) by phorbol ester (PMA) was reported previously to increase total binding of the peptide in whole rat pituitary cells. The effect could be obtained in cells from intact, not from spayed animals, suggesting a different level of spontaneous phosphorylation in both conditions. In the present work, endogenous PKC was desensitized in pituitary cells sampled from intact or 3 weeks castrated male rats and maintained in primary culture. Desensitization was induced by overnight incubation with 1 microM PMA. The maximum number of plasma membrane LHRH receptors (Bmax) present on cells from in intact animals was higher (+ 98 +/- 9%) when binding was performed at 0.5 degrees C instead of 21 degrees C as already observed in non PKC-desensitized cells. PMA (100 nM) was ineffective to increase Bmax, suggesting effectiveness of enzyme desensitization. In contrast, ionomycin 1 microM increased Bmax (53 +/- 10%). This increment was inhibited by W7, a calmodulin inhibitor, with an IC50 = 1 +/- 0.35 10(-6) M. No temperature dependency of the Bmax was observed in cells from castrated rats as already shown in the absence of PKC desensitization. Under these conditions, a Bmax decrease of 34 +/- 6% and 36.5 +/- 7.5% respectively was observed in the presence of H7, a PKC inhibitor, or of W7 (IC50 = 1 +/- 0.5 10(-5) M and IC50 = 0.8 +/- 0.2 10(-6) M). We conclude that a Ca2+ calmodulin dependent protein kinase rather than PKC itself is responsible for unmasking LHRH receptors.
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PMID:A Ca2+ calmodulin dependent kinase rather than protein kinase C is involved in up-regulation of the LHRH receptor. 131 37

This study investigates the signaling pathways that lead to acute augmentation of secretagogue-induced LH secretion, the physiologically relevant manifestation of which is LHRH self-potentiation. The consequence of LHRH self-potentiation is an augmented LH secretory response to subsequent exposure to the peptide. Although the mechanism for LHRH self-potentiation remains obscure, the second messenger cAMP and the steroid hormone progesterone share common characteristics in their acute augmentation of secretagogue-induced pituitary LH secretion, suggesting that cross-talk between the peptide and steroid hormone pathways may occur. The progesterone receptor would represent a point of convergence of several effectors known to augment secretagogue-induced LH secretion. In rat anterior pituitary cells cultured in the absence of progesterone, it was found that the progesterone receptor antagonist RU486 (2 nM) inhibits LHRH self-potentiation induced by hourly pulses of 1 nM LHRH. In the absence of added progesterone, RU486 also suppresses the augmentation of LHRH-stimulated LH secretion which is a consequence of increasing [cAMP]i with either 8-bromo-cAMP (1 mM) or forskolin (1 microM) treatment. The extent of the suppression of the cAMP action in the presence of RU486 is similar to that found with the RNA synthesis inhibitor, actinomycin D. The data are consistent with the hypothesis that a LHRH-stimulated protein kinase A cascade acts, in part, through transcriptional activation of the progesterone receptor. It is concluded that the mechanism of LHRH self-potentiation requires cross-talk with the progesterone receptor.
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PMID:A pathway for luteinizing hormone releasing-hormone self-potentiation: cross-talk with the progesterone receptor. 131 80

The mechanisms of LH release and desensitization of the pituitary are still poorly known. We investigated the release of LH by dispersed rat pituitary cells, which were cultured with cytodex beads, packed into columns and superfused. The following results were obtained. 1) LH secretion was rapidly decreased by continuous infusion of 10(-8) M LHRH reaching the control level within 3-4 hours. The desensitization was also observed when the pulse amplitude of LHRH was more than 10(-7) M or when the pulse frequency was more than 4 times per hour. 2) Even after this continuous infusion of 10(-8) M LHRH, pituitary cells responded to 10(-6) M LHRH, 50 mM K+ and 3 mM 8-bromo-cAMP. 3) 3 mM 8-bromo-cAMP and 1 microM forskolin induced a significant increase in LH secretion. 4) 1 microM phorbol myristate acetate (PMA), 40 mu 1-oleoyl-2-acetylglycerol (OAG) and 20 microM Ca2+ ionophore (A-23187) caused a remarkable LH release. 5) 100 microM arachidonic acid (AA) caused a significant increase in LH release. However, the pretreatment with a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA) abolished the LH response to AA. These results indicated that protein kinase A, protein kinase C and the Ca2(+)-AA system were involved in the mechanisms of LH secretion from the pituitary respectively, and the desensitization by LHRH was easily induced when the LHRH pulse frequency and pulse amplitude were not appropriate to pituitary stimulation.
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PMID:[Study on LH release and desensitization by means of a superfusion system with beads attached pituitary cells]. 169 60

Tissue-type plasminogen activator (tPA) is secreted by rat granulosa cells in response to treatment with activators of protein kinase A (follitropin, FSH), protein kinase C (gonadotropin-releasing hormone, GnRH) and tyrosine kinase (epidermal growth factor, EGF). Because steroid hormones have been shown to enhance the gonadotropin stimulation of ovarian differentiation, we investigated the effects of steroid hormones, alone or together with various kinase activators, on tPA activities and mRNA levels in cultured rat granulosa cells. Treatment of cells with dexamethasone (DEX; a glucocorticoid agonist) or R1881 (an androgen agonist) caused an increase in tPA secretion and mRNA levels. In addition, the stimulation of tPA activity and mRNA levels by FSH (50 ng/ml) was synergistically enhanced by cotreatment with DEX or R1881 in a time-dependent manner with 2.8- and 1.6-fold increase at 9 h after incubation as compared to cells treated with FSH alone. In contrast, treatment with diethylstilbestrol had no effect on tPA levels. Furthermore, tPA activity and mRNA levels induced by GnRH and EGF were also increased by cotreatment with DEX or R1881 as compared with cells treated with GnRH or EGF alone. Likewise, the stimulation of tPA mRNA levels by dibutyryl cAMP, a protein kinase A activator, and phorbol myristate acetate (PMA), a protein kinase C activator, was enhanced by cotreatment with DEX or R1881. These results demonstrate that glucocorticoid and androgen enhance tPA secretion and mRNA levels stimulated by FSH, GnRH and EGF in granulosa cells. The rat granulosa cells provide a useful model for studying the mechanism of regulation of tPA gene expression by steroid hormones.
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PMID:Synergistic effect of glucocorticoids and androgens on the hormonal induction of tissue plasminogen activator activity and messenger ribonucleic acid levels in granulosa cells. 210 7

1. Neurones dissociated from Rana pipiens paravertebral sympathetic ganglia were studied by means of the whole-cell patch-clamp technique. Responses to agonists were best recorded when cyclic AMP was included in the patch pipette. 2. Two populations of cells were identified on the basis of size (input capacitance, Cin) and the presence or absence of a fast, transient outward current (A-current, IA). This current was usually present in the 'large' cells (Cin = 40.5 +/- 1.5 pF, n = 66) but absent from 'small' cells (Cin = 21.0 +/- 0.8 pF, n = 70). 3. Both cell types exhibited a slowly activating, non-inactivating K+ current (M-current, IM) which was suppressed by luteinizing hormone-releasing hormone (LHRH, 10-100 microM). Threshold for activation of IM was about -75 mV, half-maximal activation was at -50 mV and the M-conductance GM increased e-fold for at 7 mV change in membrane potential. The maximum value for IM studied in large cells by patch-clamp procedures was less than 0.2 nA. More M-channels were available per unit membrane area in the small cells (GM = 1495 microS cm-2) than in the large cells (GM = 1034 microS cm-2). Time constants for IM deactivation at -70 mV were faster in the large cells (37.2 +/- 4.6 ms, n = 16) than in the small cells (66.1 +/- 5.9 ms, n = 9). 4. Muscarine (10 microM) produced inward current in the large cells as a result of IM suppression. In 40% of the large cells, some of the M-channels were also sensitive to adrenaline (10-100 microM). In a few large cells (less than 10%) adrenaline produced outward current by increasing IM. 5. Muscarine failed to effect IM in the small cells and instead produced an inwardly rectifying K+ current which activated within 5 ms at -110 mV. The outward current produced in twenty out of thirty-seven small cells by adrenaline was occluded by that produced by muscarine, suggesting that both agonists affect the same K+ channels. 6. Inclusion of the protein kinase inhibitors, 1-(5-isoquinolinyl-sulphonyl)-2-methyl piperazine (H-7, 50 microM) or gold sodium thiomalate (GST, 50 microM) in the pipette solution failed to antagonize either muscarine-induced current. Both currents were prolonged when the 'internal solution' contained GTP-gamma-S (50 microM). 7. Phorbol-12-myristate-13-acetate (PMA, 2-5 microM) produced an inward current as a result of IM suppression in both small and large cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of muscarine and adrenaline on neurones from Rana pipiens sympathetic ganglia. 221 86

We investigated the role of Ca2+/phospholipid-dependent protein kinase (protein kinase C) in LH secretion using rat anterior pituitary pieces obtained at known stages of the estrous cycle and superfused in vitro. Secretagogues were administered as 10-min (LHRH) or 30-min (all others) pulses. Activation of protein kinase C with phorbol 12-myristate 13-acetate (PMA) results 2 h later in an amplification of LHRH-induced LH secretion in a concentration (1 nM to 1 microM)-and protein synthesis-dependent manner in proestrous, but not estrous, pituitaries; the diacylglycerol analog 1-oleoyl-2-acetylglycerol (OAG) also augments subsequent LHRH-induced secretion. At 1 microM, PMA alone increases the LH secretory rate, but with a pattern different from that induced by LHRH; the characteristics of the PMA response are affected by prior exposure to LHRH, estrous cycle stage, and cycloheximide. Pretreatment with either 8-bromo-cAMP or forskolin results in augmentation of subsequent LHRH-induced secretion without affecting baseline secretion. If the cells are exposed simultaneously to forskolin and OAG, but not 8-bromo-cAMP and OAG, the augmentation is dampened. This preliminary result suggests a possible interaction between protein kinase C and cAMP-dependent protein kinase in LH secretion regulation. We conclude that, regarding initiation of LH release, protein kinase C appears to be but one of a complex of mediators required for the secretory response to LHRH. Regarding the amplification of LHRH-induced release, activation of protein kinase C may be a component of the LHRH self-priming response.
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PMID:Modification of luteinizing hormone secretion by activators of Ca2+/phospholipid-dependent protein kinase. 300 47

The stimulation of steroid production in Leydig cells by LH is accompanied by increased cyclic AMP levels, activation of protein kinase A, increased phosphorylation of at least six phosphoproteins and requires protein synthesis. However, an LH-releasing hormone agonist (LHRH-A) can stimulate steroid production without stimulation of cyclic AMP levels. In the present study we have shown that LH action involves calcium fluxes through the plasma membrane, in addition to activation of protein kinase A. The action of LHRH-A, in contrast, does not require calcium fluxes and is not potentiated by 1-methyl-3-isobutylxanthine, indicating that cyclic AMP is not involved. Extracellular calcium is required for the action of both LH and LHRH-A. An increase in intracellular calcium concentration due to the effect of ionophore A23187 did not stimulate steroidogenesis and had deleterious effects on intracellular adenosinetriphosphate levels. LH and 4 beta-phorbol-12-myristate-13-acetate (PMA), an activator of protein kinase C, both stimulated phosphorylation of proteins of 17 000 and 33 000 mol. wt, whereas LHRH-A had no effect. However, compared with the effect of LH, PMA had a much smaller effect on steroid production, indicating that even if protein kinase C may be activated by LH its role in the regulation of steroid production may be less important than the role of protein kinase A. Action of LHRH-A does not appear to be mediated by calcium fluxes, protein kinase C activation or active protein phosphorylation.
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PMID:Effects of LH and an LH-releasing hormone agonist on different second messenger systems in the regulation of steroidogenesis in isolated rat Leydig cells. 300 76

The demonstration that activators of the Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C), such as phorbol esters and diacylglycerols, can provoke luteinizing hormone (LH) release from pituitary gonadotropes, suggests a possible role for protein kinase C in stimulus-release coupling. We now report that administration of phorbol myristate acetate (PMA) to pituitary cell cultures causes a sustained reduction in Triton X-100-extracted protein kinase C activity. Further, phorbol ester- and diacylglycerol-stimulated LH release, as well as inhibition by PMA of gonadotropin-releasing hormone (GnRH)-stimulated inositol phosphate production, were reduced by pretreatment with PMA. The effects of phorbol ester pretreatment on PMA-stimulated LH release and protein kinase C activity were dose-dependent, sustained (greater than or equal to 24 h) and specific (no measurable effect with 4 alpha-phorbol didecanoate). The effect on PMA-stimulated LH release was apparently Ca2+-independent. In pituitary cell cultures with reduced protein kinase C activity, the gonadotropes have reduced responsiveness to PMA but release a similar proportion of cellular LH in response to Ca2+-mobilizing secretagogues (GnRH and A23187) as do control cells. The normal responsiveness to GnRH of cells with reduced responsiveness to protein kinase C activators calls into question the requirement for this enzyme for GnRH-stimulated LH release.
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PMID:Phorbol esters reduce gonadotrope responsiveness to protein kinase C activators but not to Ca2+-mobilizing secretagogues. Does protein kinase C mediate gonadotropin-releasing hormone action? 310 28

This study investigates the hypothesis that stimulation of ovarian progesterone (P) production by LHRH is mediated in part by arachidonic acid (AA). In rat granulosa cells prelabeled with [3H]AA or [3H]inositol, treatment with LHRH stimulates the accumulation of radiolabeled inositol phosphosphates, diacyglycerol, and unesterified AA. Treatment with AA (3 X 10(-7)-10(-5) M) enhances P production in a dose-dependent manner. Concurrent treatment with AA and LHRH (or a LHRH agonist) further stimulates P production. The stimulatory effect of AA on P production, either alone or in combination with LHRH, could be seen as early as 3 h after AA addition. Addition of a phorbol ester, 12-O-tetracecanoylphorbol-13-acetate (TPA), to granulosa cells stimulates P production. Interestingly, the concomitant presence of AA and TPA further enhances production compared with either TPA or AA treatment alone. The stimulatory effect of AA on P production is completely abolished by nordihydroguaiaretic acid, but not by indomethacin. On the other hand, addition of nordihydroguaiaretic acid (but not indomethacin) reduces LHRH-stimulated P levels by about 50%. Nordihydroguaiaretic acid, as well, markedly attenuates the P response due to combined treatment with LHRH and AA. Taken together, these results strongly support the notion that AA (or its lipoxygenated metabolites) partially mediates the action of LHRH. Along with the calcium and protein kinase-C pathways, AA metabolism may be involved in the biological actions of LHRH in the ovary.
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PMID:Role of arachidonic acid in luteinizing hormone-releasing hormone action: stimulation of progesterone production in rat granulosa cells. 312 44

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


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