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)

TRH and GnRH receptors are each coupled to G proteins of the Gq/11 family. Activation of each of these receptors by their respective ligands results in the stimulation of phospholipase C activity, leading to calcium mobilization and protein kinase C activation. Thus, the effects of TRH and GnRH may be mediated through the same intracellular signal transduction pathway. To compare responses to TRH and GnRH directly within one cell type, we have stably transfected the rat pituitary GH3 lactotrope cell line, which expresses the endogenous TRH receptor, with an expression vector containing rat GnRH receptor cDNA. Transfected cells specifically bound GnRH with high affinity and responded to GnRH stimulation with an increase in PRL mRNA levels, analogous to their response to TRH stimulation. Stably transfected GH3 cells, which were then transiently transfected with luciferase reporter constructs containing either the PRL or the glycoprotein hormone alpha-subunit promoter, responded to either GnRH or TRH stimulation with an increase in luciferase activity in a time- and dose-dependent fashion. The stimulatory effects of maximally effective concentrations of TRH and GnRH were additive on PRL, but not alpha-subunit, gene expression. These data, coupled with evidence of cross-desensitization of alpha-subunit, but not PRL, promoter activity stimulation by TRH and GnRH, suggest that there may be differences in the signal transduction pathways activated by TRH and GnRH receptors in the regulation of PRL and alpha-subunit gene expression.
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PMID:Evidence that signalling pathways by which thyrotropin-releasing hormone and gonadotropin-releasing hormone act are both common and distinct. 752 98

Several investigations have suggested that sphingosine (SP) derivatives are potent inhibitors of protein kinase C. In GH4C1 cells, protein kinase C is a potent modulator of voltage-operated calcium channels (VOCCs). The aim of the present study was to investigate whether SP derivatives could modify calcium entry via VOCCs. Using fura-2-loaded cells and 45Ca2+ flux studies, we show that several SPs potently and rapidly inhibit depolarization-evoked calcium entry in a dose-dependent manner. The effect was not due to an enhanced efflux of calcium from the cells, as the depolarization-evoked entry of Ba2+ was inhibited by the SPs. A similar inhibition was observed with 1,2-dioctanoylglycerol, an activator of sphingomyelinase in GH3 cells. Phorbol myristate acetate and 1-oleyl-2-acetylglycerol had only a modest inhibitory effect. Furthermore, whole cell patch-clamp experiments showed that sphingosinephosphorylcholine (SPC) potently attenuated calcium entry via VOCCs. In experiments using cells grown on coverslips, we found that the inhibitory effect of SPC on calcium entry was reversible. The addition of sphingomyelinase or hexanoyl ceramide, a cell-permeable ceramide, only modestly inhibited the depolarization-evoked entry of calcium, whereas arachidonic acid and phosphatidic acid had no effect. The SP metabolite sphingosine-1-phosphate had no effect on the entry of calcium. The results suggest that the effects of the SPs were probably not the result of a conversion to ceramide or of the production of other lipid second messengers. In cells with down-regulated protein kinase C, SPC, SP, and 1,2-dioctanoylglycerol inhibited depolarization-evoked calcium entry, suggesting that the inhibition was independent of an action mediated via protein kinase C. The SPs per se did not induce any changes in intracellular free calcium, and they did not inhibit the TRH-evoked release of sequestered calcium in the cells. However, TRH-evoked calcium entry was inhibited. The results suggest that SPs are potential regulators of calcium entry mediated by VOCCs in GH4C1 cells.
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PMID:Sphingosine derivatives inhibit depolarization-evoked calcium entry in rat GH4C1 cells. 758 22

This study reports a direct effect of TRH on amylase secretion from isolated rat exocrine pancreatic acinar cells. TRH inhibited carbachol (10(-5) M)-stimulated amylase secretion by a maximum of 24% at a concentration of 10(-11) M (p < 0.05), but did not affect basal amylase release in concentrations from 10(-13) M to 10(-8) M. Ceruletide (3 x 10(-10) M)-stimulated amylase secretion was maximally reduced by 23% at a TRH concentration of 10(-10) M (p < 0.05). Direct stimulation of protein kinase C-mediated secretion by the diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) was not altered by TRH. The TRH metabolite cyclo (His-Pro) did not influence basal or stimulated pancreatic secretion in vitro. These findings point to a TRH-mediated modulation of exocrine pancreatic secretion at the receptor site.
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PMID:Inhibitory effect of thyrotropin-releasing hormone on enzyme secretion from isolated rat pancreatic acinar cells. 759 Jun 25

Membrane capacitance measurements were used to study neuropeptide modulation of exocytosis by perforated patch clamped rat lactotrophs. We report that depolarizing voltage-clamp pulses evoke exocytosis that is steeply dependent on Ca2+ influx through voltage-gated Ca2+ channels. Furthermore, we find that the neuropeptide TRH (thyrotropin-releasing hormone) acts in three phases to promote exocytosis. First, TRH transiently (within approximately 0.5 min) triggers depolarization- and extracellular Ca(2+)-independent exocytosis. Second, within 3 min of application, TRH facilitates depolarization-evoked exocytosis while inhibiting voltage-gated Ca2+ current. Finally, after 8 min, TRH further enhances depolarization-evoked exocytosis by increasing high-voltage-activated (HVA) Ca2+ channel current. Activation of protein kinase C (PKC) with a phorbol ester also stimulates depolarization-evoked exocytosis by increasing Ca2+ current. Therefore, PKC can only account for the last effect of TRH. Thus, a single neuromodulator may employ several temporally distinct mechanisms to stimulate peptide secretion.
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PMID:Three phases of TRH-induced facilitation of exocytosis by single lactotrophs. 762 27

The hypothalamic neuropeptide TRH, which stimulates prolactin (PRL) release and PRL gene transcription, also raises c-fos proto-oncogene mRNA levels in GH3B6 rat pituitary cells. C-fos is assumed to be involved in the transduction of external signals to the nucleus as a component of AP1 transcription factor, a protein complex that contains a member of the jun proto-oncogene family. We have thus looked for the member(s) of the jun family that could be the partner of c-fos in TRH-stimulated GH3B6 cells. The common biphasic pattern of jun B and c-fos mRNA regulation under TRH exposure, i.e., an early peak and a long-lasting plateau phase, suggested that jun B was the best candidate. Then, to better understand the mode of action of TRH and to look for possible functions of c-fos and jun B in these cells, we have investigated the role of different intracellular signalings in the induction of each proto-oncogene. This was done taking as a model that the effects of TRH on PRL release and PRL gene transcription has been previously ascribed to the coupling of the TRH receptor to the activation of both protein kinase C- and calcium-dependent mechanisms. An extensive pharmacological analyses revealed that PKC-, Ca2+ but also protein kinase A-dependent mechanisms are involved in TRH-induced c-fos and jun B mRNA early responses in GH3B6 cells. The overall study also revealed specific features in the control by TRH of each proto-oncogene by some intracellular messengers. Finally, considering the fact that second long lasting phase of proto-oncogene expression was found associated with increased PRL mRNA accumulation whatever the stimulus, it might be proposed that AP1 [c-Fos/Jun B] factor could be involved in the regulation of PRL gene expression. Such hypothesis was furthermore supported by preliminary gel-shift experiments. Nevertheless, in view of the systematic coincidence between acute PRL release and early proto-oncogene induction, a role for c-fos and jun B in the control of genes involved in the secretory process might also be suggested.
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PMID:[Stimulation of C-fos and jun B proto-oncogenes: potential role of TRH effects in clone cell line with prolactin (GH3B6)]. 764 71

Numerous transmitter receptors are linked via GTP-binding proteins (G proteins) to membrane phosphoinositide metabolism by phospholipase C (PLC) and generation of second messengers such as activated protein kinase C (PKC), inositol trisphosphate (IP3) and/or elevations in intracellular calcium. In many cases, these same receptors also inhibit a resting ('leak') potassium current (IK(L)), thereby depolarizing neurons. It is unclear if activation of this PLC pathway mediates inhibition of IK(L) by neurotransmitter receptors. Therefore, we tested the contribution of this pathway to the TRH-induced inhibition of IK(L) in rat hypoglossal motoneurons (HMs) using conventional intracellular recording in brainstem slices. When HMs were recorded with electrodes containing 3 M KCl or 30 mM GTP (in KCl), TRH induced a depolarization that recovered quickly (within 8-10 min) and could be repeated with only modest tachyphylaxis (< 20%). However, with electrodes containing the non-hydrolyzable G protein activator, GTP gamma S (10 mM), the TRH-induced depolarization was long lasting (up to 1 h); with electrodes containing the G protein inhibitor, GDP beta S (20 mM) the tachyphylaxis with repeated TRH application was exaggerated (approximately 60%). Activation of PKC by phorbol dibutyrate (10 microM in perfusate) neither mimicked nor occluded the effects of TRH. There were no effects on membrane potential, input resistance (RN) or the response to TRH in HMs during long recordings with electrodes containing high concentrations of IP3 (60 mM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of thyrotropin-releasing hormone on rat motoneurons are mediated by G proteins. 770 7

Harvesting MDCK cells with trypsin-EDTA reduces potassium currents (IK) to a mere 10%, presumably by hydrolysis of K+ channels, but replating at confluence restores them in 12-18 hr, through a process that requires transcription, translation and exocytic fusion of intracellular membrane vesicles to the plasma membrane (Ponce & Cereijido, 1991; Ponce et al., 1991a). In the present work we find that this restoration of IK also requires cell-cell contacts and the presence of 1.8 mM Ca2+. The role of extracellular Ca2+ may be substituted by 2.0 microM TRH, 10 nM PMA or 200 micrograms/ml DiC8. drugs that stimulate the system of phospholipase C (PLC) and protein kinase C (PKC). Conversely, the recovery of IK triggered by Ca-dependent contacts can be blocked by 110 microM neomycin, 2.0 microM H7, and 250 nM staurosporine, inhibitors of PLC and PKC. These results suggest that the expression of new K+ channels depends on Ca(2+)-activated contacts with neighboring cells and that the information is conveyed through PLC and PKC, a process in keeping with changes in its enzymatic activity and cellular distribution of PKC. Plasma membrane is also reduced and restored upon harvesting and replating, and depends on Ca(2+)-activated contracts. However, the effects of the chemicals tested on IK differ from the ones they elicit on the recovery of plasma membrane, suggesting that cells can independently regulate their population of K+ channels and the surface of their membrane.
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PMID:Expression of potassium channels in epithelial cells depends on calcium-activated cell-cell contacts. 776 7

The role of cytosolic free Ca2+ ([Ca2+]i) in the induction of the immediate early gene c-fos by TRH or by phorbol 12-myristate 13-acetate (PMA) was studied in the clonal pituitary cell line GH4C1. It was found that c-fos mRNA levels were rapidly and transiently increased by TRH at physiological concentrations (1-100 nM). The effect of TRH was dependent on a rise in [Ca2+]i, and TRH stimulation of Ca2+ influx was essential for c-fos induction. Cell depolarization with K+, which produces a [Ca2+]i rise by soliciting Ca2+ influx via voltage-gated Ca2+ channels, was insufficient to induce c-fos. Blockade or downregulation of protein kinase C (PKC) strongly attenuated TRH stimulation of c-fos expression. Direct stimulation of PKC by PMA raised c-fos mRNA levels, but only under conditions permitting Ca2+ influx. We conclude that TRH induces c-fos mRNA by a mechanism dependent on PKC activation and on Ca2+ influx. The essential role of Ca2+ influx for PMA stimulation of c-fos mRNA suggests a novel pathway linking PKC stimulation to early gene expression.
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PMID:Induction of c-fos in pituitary cells by thyrotrophin-releasing hormone and phorbol 12-myristate 13-acetate depends upon Ca2+ influx. 789 48

The effects of two cryptic peptides from pro-TRH: Ps4 (160-169) and Ps5 (178-199) were investigated on basal and secretagogue (GRH and TRH)-induced releases of GH from perifused fragments of rat adenohypophysis. Validation of the perifusion system was done by measuring: (1) the dose-dependent effect of GRH and TRH on GH release; and (2) the stimulation of that release by forskolin (to mimic the adenylate cyclase pathway) or by phorbol ester (to mimic the protein kinase C pathway). We show that: (1) Ps4 and Ps5 (1 microM) do not modify basal GH release; (2) Ps4 (1 microM) changes neither GRH (10 nM)- nor TRH (100 nM)-induced release of GH; (3) Ps5 (100 nM and 1 microM) significantly decreases the release of GH induced by equimolar concentrations of TRH but not that induced by GRH.
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PMID:A cryptic peptide of TRH prohormone inhibits TRH-induced GH release. 799 14

We studied the effect of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interferon-gamma (IFN-gamma) on the function of thyroid cells and pituitary thyrotrophs. In FRTL-5 rat thyroid cells, both human and murine TNF-alpha inhibited basal and TSH-stimulated [125I]iodide transport. IL-1 shared this action with TNF-alpha, but was less potent. IL-1 and IFN-gamma did not cause a further reduction of TNF-alpha-induced inhibition of [125I]iodide transport. TNF-alpha, phorbol ester 12-myristate 13-acetate (PMA), and calcium ionophore (CI) A23817 all inhibited [125I]iodide transport, but high doses of PMA and CI also blocked the inhibitory action of TNF-alpha on [125I]iodide transport. Inhibition of protein kinase A and protein kinase C by H7 or HA inhibited TSH-stimulated iodide transport, but did not block the TNF-alpha action, suggesting that the mechanism of TNF-alpha action on thyroid cells is independent of protein kinase A and C. In pituitary cells, both human and murine TNF-alpha did not affect basal TSH secretion, but TNF-alpha reduced TRH-stimulated TSH secretion. This study provides further in vitro evidence that TNF-alpha inhibits the function of the hypothalamus-pituitary-thyroid axis acting directly on both the pituitary and thyroid glands.
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PMID:Suppression of rat thyrotroph and thyroid cell function by tumor necrosis factor-alpha. 811 27


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