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)

Thyrotropin-releasing hormone (TRH) stimulates biphasic prolactin (PRL) secretion from rat pituitary GH3 cells. The pretreatment of cells with EGTA (100 microM) plus arachidonic acid (15 microM), a condition which decreased TRH-responsive intracellular Ca2+ pools, eliminated the activity of TRH on burst PRL secretion (2 min) but did not alter that on sustained PRL secretion (30 min). However, the treatment of cells with EGTA, arachidonic acid and H-7 (300 microM), a potent inhibitor of protein kinase C (PKC), almost completely suppressed the activity of TRH for sustained PRL secretion. In cells down-modulated for PKC, TRH abolished this Ca2(+)-independent sustained PRL secretion. These results suggest that TRH acts through a separate, Ca2(+)-independent secretory mechanism, besides by modulating the Ca2(+)-dependent mechanism and that PKC is involved in this Ca2(+)-independent secretory pathway.
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PMID:Ca2(+)-independent secretory mechanism of thyrotropin-releasing hormone (TRH) involves protein kinase C in rat pituitary cells. 212 86

4 beta phorbol-12, 13-dibutyrate (PDBu) stimulated cyclic AMP accumulation in GH3 pituitary tumour cells in the presence of isobutylmethylxanthine. This effect persisted after preincubation of cells with cholera or pertussis toxins. In contrast, vasoactive intestinal polypeptide (VIP)-stimulated cyclic AMP accumulation was inhibited by PDBu in a dose dependent fashion (IC50 = 5.1 nM). Thyroliberin (TRH) had a similar, but non-additive, stimulatory effect on cyclic AMP accumulation with PDBu, however it did not inhibit VIP stimulation. These results suggest that TRH may stimulate cyclic AMP accumulation through protein kinase C and that stimulation of adenylate cyclase by PDBu and TRH may occur distal to the guanine nucleotide binding regulatory proteins, Ns and Ni.
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PMID:Modulation of cyclic AMP accumulation in GH3 cells by a phorbol ester and thyroliberin. 240 70

Prolactin (PRL) release in permeable GH3 pituitary cells was stimulated by the protein kinase C activators 12-O-tetradecanoylphorbol 13-acetate (TPA) and 1-oleoyl-2-acetyl-sn-glycerol (OAG). Both agents stimulated secretion at 10 nM Ca2+, but higher [Ca2+] (greater than 0.1 microM) potentiated TPA and OAG action. Maximal potentiation occurred at 1 microM calculated free Ca2+, and a similar value was obtained when the cytoplasmic [Ca2+] was measured with the Ca2+-sensitive dye Quin 2. Release of a secretory sulfated proteoglycan was also stimulated by TPA and OAG in permeable GH3 cells, with characteristics similar to those for PRL release. Trifluoroperazine, polymyxin B, neomycin, and 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate all inhibited both TPA- and Ca2+-stimulated PRL release, but in each case the half-maximal inhibitory concentrations were approximately 2-fold higher for TPA-stimulated release compared to Ca2+-stimulated release. Thyrotropin-releasing hormone (TRH) and guanosine 5'-Q-thiotriphosphate, which stimulate polyphosphoinositide breakdown in permeable cells, were found to be only weak stimulators of PRL release, compared to TPA and exogenous diacylglycerol. However, a much stronger effect of TRH was seen if cells were briefly treated with TRH prior to permeabilization. PRL release from TRH-pretreated permeable cells resembled TPA- and OAG-stimulated secretion, with [Ca2+] greater than 0.1 microM potentiating the effect of TRH pretreatment. These studies support the hypothesis that PRL release in GH3 cells can be stimulated directly by a diacylglycerol-activated secretory mechanism whose activity is modulated by [Ca2+].
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PMID:Characterization of phorbol ester- and diacylglycerol-stimulated secretion in permeable GH3 pituitary cells. Interaction with Ca2+. 301 2

Thyrotropin-releasing hormone (TRH) induces rapid and transient conversion of protein kinase C (Ca2+/phospholipid-dependent enzyme) from a soluble to a particulate-bound form in GH4C1 rat pituitary cells. Ionomycin (200 nM), a calcium ionophore, had no effect by itself on the subcellular distribution of protein kinase C. However, pretreatment of the cells with 200 nM ionomycin inhibited by greater than 50% the ability of TRH to cause translocation of protein kinase C from the cytosol to the particulate cell fraction. Inhibition by ionomycin required that the cells be incubated with the ionophore for at least 10 s before TRH addition. Ionomycin pretreatment did not alter the kinetics of TRH-induced protein kinase C redistribution. Incubation of the cells with 43 mM potassium prior to TRH addition almost completely reversed the inhibition induced by ionomycin. We propose that the mechanism by which ionomycin attenuates TRH action on protein kinase C may involve the capacity of the ionophore to empty the intracellular calcium reservoir which normally releases calcium into the cytosol in response to TRH. Our result provides evidence that the rise in intracellular calcium, which accompanies diacylglycerol formation following TRH action on polyphosphatidylinositide hydrolysis, may be required to achieve maximal conversion of protein kinase C to its presumed active, membrane-bound form in these cells.
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PMID:Ionomycin inhibits thyrotropin-releasing hormone-induced translocation of protein kinase C in GH4C1 pituitary cells. 311 Jan 61

Tissue specificity of the Thyroliberin (TRH)- and 12-O-tetradecanoylphorbol 13-acetate (TPA)-sensitive adenylyl cyclase has been studied using normal or neoplastic organ samples or cells from the pituitary gland, stomach, prostate, myocardium, liver and bone. It appeared that TRH stimulates the adenylyl cyclase in both normal (basal cells), hyperplastic and adenocarcinomatous prostate as well as in the pituitary and stomach. TPA also stimulated the enzyme from the prostate and other organs/cells, but to a greater extent in neoplastic tissue. Functional links from protein kinase C to adenylyl cyclase and from protein kinase C to tyrosine kinase/oncogene expression have been established. Hence it is believed that TRH, which stimulates the adenylyl cyclase and protein kinase C in the pituitary, may serve as a factor contributing to transformation of prostatic cells or enhanced cell proliferation in prostatic cancer.
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PMID:Distribution of Thyroliberin (TRH)- and 12-O-tetradecanoylphorbol 13-acetate (TPA)-activated adenylyl cyclase in normal and neoplastic tissue with special reference to the prostate. 314 32

Thyrotropin-releasing hormone (TRH) affects hormone secretion and synthesis in GH4C1 cells, a clonal strain of rat pituitary cells. Recent evidence suggests that the intracellular mediators, inositol 1,4,5-trisphosphate and 1,2-diacylglycerol, which are generated as a result of TRH-induced hydrolysis of the polyphosphatidylinositols, may be responsible for some of the physiological events regulated by TRH. Because diacylglycerol is an activator of protein kinase C, we have examined a role for this enzyme in TRH action. The subcellular distribution of protein kinase C in control and TRH-treated cells was determined by measuring both enzyme activity and 12,13-[3H]phorbol dibutyrate binding in the cytosol and by measuring enzyme activity in the particulate fraction. Acute exposure of GH4C1 cells to TRH resulted in a decrease of cytosolic protein kinase C, and an increase in the level of the enzyme associated with the particulate fraction. The redistribution of protein kinase C induced by TRH was dose- and time-dependent, with maximal effects occurring within the first minute of TRH treatment. Analogs of TRH which do not bind to the TRH receptor did not induce redistribution of protein kinase C, while the active analog, methyl-TRH, did promote redistribution. Treatment of GH4C1 cells with phorbol myristate acetate also resulted in a shift in protein kinase C distribution, although the response was slower than that produced by TRH. TRH-induced redistribution of protein kinase C implies translocation of the enzyme from a soluble to a membrane-associated form. Because protein kinase C requires a lipid environment for activity, association with the membrane fraction of the cell suggests activation of the enzyme; thus, protein kinase C may play a role in some of the actions of TRH on GH4C1 cells.
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PMID:Thyrotropin-releasing hormone induces redistribution of protein kinase C in GH4C1 rat pituitary cells. 315 31

Thyrotropin-releasing hormone (TRH) is a tripeptide that rapidly enhances prolactin secretion in clonal, hormone-responsive GH3 rat pituitary cells. In an effort to identify postreceptor mechanisms for TRH, protein phosphorylation studies have been conducted. Our previous studies (Drust, D.S., Sutton, C.A., and Martin, T. F. J. (1982) J. Biol. Chem. 257, 3306-3312; Drust, D.S., and Martin, T. F. J. (1982) J. Biol. Chem. 257, 7566-7573) showed that TRH rapidly (less than 15 s) increased the phosphorylation of at least six cytosolic proteins (41K (Mr = 41,000), several 59K, 65K, 82K, and 97K) and, with a 5- to 10-min latency, increased the phosphorylation of a seventh (80K). Cyclic AMP did not appear to mediate TRH-stimulation of protein phosphorylation; in contrast, Ca2+ translocation and Ca2+-dependent protein phosphorylation accounted for hormone-induced changes in 97K (and possibly 41K) phosphorylation. The studies reported here indicate that lipid (diacylglycerol) accumulation and protein kinase C activation mediate TRH-stimulated phosphorylation of the additional five cytosolic proteins (two 59K, 65K, 80K, and 82K). This conclusion is based on the findings that: 1) phospholipase C treatment, which produces diacylglycerol, mimicked several TRH effects; 2) bombesin, another peptide that induces inositol phosphatide turnover, mimicked several TRH effects; 3) phorbol esters, which were shown to activate GH3 cell protein kinase C directly, produced TRH-like effects; 4) partially purified GH3 cell cytosolic protein kinase C was activated by diacylglycerol; and 5) 59K and 82K proteins were endogenous in vitro substrates for a cytosolic lipid-stimulated protein kinase. We conclude that rapid TRH effects in promoting inositol phosphatide turnover in GH3 cells may be linked to the activation of protein phosphorylation mediated by protein kinase C. These, and previously reported studies, indicate a role for Ca2+ and lipids (diacylglycerol) as dual intracellular messengers for TRH.
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PMID:Thyrotropin-releasing hormone rapidly activates protein phosphorylation in GH3 pituitary cells by a lipid-linked, protein kinase C-mediated pathway. 623 63

We have investigated the intracellular mechanisms underlying thyrotropin-releasing hormone (TRH)-mediated [3H]dopamine ([3H]DA) release from dispersed rat tuberoinfundibular dopaminergic (TIDA) neurons. The specific binding of [3H]Me-TRH to these cells is characterized by a single, high-affinity binding site (Kd = 1.2 nM) with a Bmax value of 178 fmol/mg protein. Thyrotropin-releasing hormone markedly increased [3H]DA release and intracellular free calcium concentration ([Ca2+]i) in TIDA neurons, and its effect was abolished by treatment with EGTA (5 mM) or chlordiazepoxide, a specific TRH receptor antagonist (10 microM). Furthermore, to examine the involvement of protein kinase C on [3H]DA release, we investigated the effect of phorbol myristate acetate (PMA), which is known to activate protein kinase C directly. Phorbol myristate acetate induced a significant increase in [3H]DA release in a concentration-dependent manner. Treatment with TRH (1 microM) plus PMA (100 nM) resulted in an additive increase in [3H]DA release. Thyrotropin-releasing hormone (1 microM) still increased [3H]DA release even after preincubation with PMA (500 nM) for 24 h, but PMA (100 nM) did not under the same conditions. These results suggest that TRH may induce DA release in dispersed rat TIDA cells by increasing calcium influx and activating the protein kinase C system.
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PMID:Effects of thyrotropin-releasing hormone and phorbol ester on dopamine release from dispersed rat tuberoinfundibular dopaminergic neurons. 823 33

We have previously found that the D5 dopamine receptor couples to a G-protein other than Gsalpha, and could be involved in signaling pathways other than regulation of adenylyl cyclase. To describe interactions of the D5 receptor with cellular effectors, we used GH4C1 cells transfected with cDNA for the human D5 receptor. Thyrotropin-releasing hormone (TRH, 100 nM) stimulated accumulation of inositol phosphates (IPs) fivefold in D5GH4C1 cells. Dopamine (DA, 10 microM) inhibited TRH-stimulated IP values by 29%; at higher concentrations (100 microM), maximal inhibition of 61% was observed. The D5 agonist SKF R-38393 (10 microM) mimicked this effect (28% inhibition). SCH 23390, a D5 antagonist, blocked the inhibition caused by both DA and SKF R-38393. Spiperone, a D2 receptor antagonist, did not block the inhibition. The D2 agonist (+/-)-2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin (PPHT) did not inhibit TRH-stimulated IP production, nor did it augment the effect of D5 agonists. The DA-mediated suppression of IP levels was not sensitive to pertussis toxin; cholera toxin blocked both TRH stimulation and DA suppression of IP accumulation in response to 100 nM TRH. Neither dibutyryl cAMP nor forskolin lowered IP formation in response to TRH. Phorbol ester decreased TRH-stimulated IP accumulation in D5GH4C1 cells; however, an inhibitor of protein kinase C (PKC) did not block the effect of DA.
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PMID:Inhibition of hormonally induced inositol trisphosphate production in Transfected GH4</ sup>C1 cells: A novel role for the D5 subtype of the dopamine receptor. 1008 53

Thyrotropin-releasing hormone (TRH) and some of its stable analogues have recently been shown to improve functional recovery after neurologic dysfunctions, such as brain trauma and epilepsy, in both animals and humans. The exact mechanism by which TRH produces its neuroprotective effects is still uncertain. The present study provides the first evidence that TRH exerts a neuroprotective effect against N-methyl-D-aspartate (NMDA)-mediated excitotoxicity in rat hippocampal slices. TRH concentration dependently reduced NMDA toxicity by a mechanism that was highly sensitive to the protein kinase C blocker, bisindolilmaleimide. Delayed application of TRH, during NMDA exposure, still produced neuroprotection.
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PMID:Neuroprotective effect of thyrotropin-releasing hormone against excitatory amino acid-induced cell death in hippocampal slices. 1032 61


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