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)

Interleukin 6 (IL-6) production was shown to be stimulated by vasoactive intestinal peptide via cAMP dependent signal transduction pathway in the pituitary. We were interested in whether other hypothalamic neuropeptides, which activate adenylate cyclase in the pituitary, also stimulate pituitary IL-6 production. Whereas vasoactive intestinal peptide was effective in stimulating pituitary IL-6 production only at concentrations of 10(-6) M or higher, pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) and calcitonin gene-related peptide (CGRP) at concentrations from 10(-10) to 10(-9) M significantly stimulated IL-6 production. Similar effective concentrations of each peptide were required for activating adenylate cyclase, as measured by extracellular cAMP accumulation. H89, a specific inhibitor of cAMP dependent protein kinase (protein kinase A), inhibited IL-6 production stimulated by PACAP38, CGRP, and (Bu)2cAMP. However, H89 failed to inhibit the IL-6 production stimulated by lipopolysaccharide, a ligand which enhanced IL-6 production in the absence of cAMP accumulation. Two other peptides which are known to activate pituitary adenylate cyclase, corticotropin-releasing factor and GRF failed to stimulate IL-6 production in pituitary cells. Using discontinuous Percoll gradients to fractionate the pituitary cells, the greatest PACAP38-stimulated IL-6 secretion was observed in the low density fraction 1 (F1). This fraction also contained the highest percentage of folliculo-stellate (FS) cells, one of the nonhormone secreting pituitary cells. However, the largest PACAP38-induced accumulation of cAMP was observed in F4. These results suggest that the production of IL-6 stimulated by PACAP and CGRP is mediated by the adenylate cyclase/protein kinase A signal transduction system. FS cells appear to be the most likely target cell type for PACAP-induced IL-6 production. However, IL-6 producing FS cells may not be an exclusive target for PACAP in the pituitary.
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PMID:Neuropeptide regulation of interleukin-6 production from the pituitary: stimulation by pituitary adenylate cyclase activating polypeptide and calcitonin gene-related peptide. 165 84

When applied to rat anterior pituitary cells, angiotensin-II (AII) exerted two opposite effects on adenylate cyclase (AC) activity: a pertussis toxin (PTX)-sensitive inhibition of the enzyme with a maximal effect of -42 +/- 2% in crude cell membrane preparations, and, in contrast, a non-PTX-sensitive stimulation of cAMP production (maximal effect = 38 +/- 3%) in intact cells. The apparent affinity of both effects was equal to 1.8 nM. The stimulation of cAMP formation parallels the stimulation of PRL release. Under the same conditions, dopamine (DA) inhibited both membrane AC activity and cAMP formation in intact cells by a PTX-sensitive mechanism. After separation of pituitary cell types by sedimentation at unit gravity, the effects of AII and DA on intracellular cAMP and membrane AC activity coincided in the same fractions (those enriched in PRL cells). The stimulatory effect of AII on cAMP formation was about 5 times weaker than that of peptides positively coupled to AC as vasoactive intestinal peptide in total as well as in PRL-enriched cells. Since the AII receptor is also coupled to phospholipase-C (PLC) in a non-PTX-sensitive manner, we investigated whether protein kinase-C (PKC) could indirectly account for the positive effect of AII on cAMP formation. 12-O-Tetradecanolylphorbol 13-acetate (TPA), a stimulator of PKC was indeed able to increase intracellular cAMP; this effect was not additive with that of AII. conversely, application of the PKC inhibitors H7 [1-(5-isoquinolylsulfonyl)2-methyl-piperazine] and staurosporine or desensitization of PKC by long exposure of the cells to TPA abolished the cAMP response to TPA as well as that to AII. In addition, thyreoliberin, another activator of the PLC pathway, was able to stimulate cAMP formation in a PKC-dependent manner. DA inhibition of intracellular cAMP was not affected by any PKC inhibition. We conclude that in lactotroph cells, 1) the AII inhibitory coupling to AC observed in membrane preparations does not exist in intact cells, at least under basal conditions; and 2) the AII intracellular cAMP stimulation observed is not accounted for by a direct coupling with AC; it is due to a cross-talk of the PLC pathway mediated by PKC, an effect that might be shared by other PLC-stimulating mediators and may participate in the regulation of PRL release.
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PMID:Involvement of protein kinase-C in the effect of angiotensin-II on adenosine 3',5'-monophosphate production in lactotroph cells. 165 95

We showed previously that TRH down-regulates TRH receptor (TRH-R) mRNA in GH3 cells by a mechanism that appears to be mediated by protein kinase C. Here we show that vasoactive intestinal peptide (VIP) down-regulates TRH-R mRNA and present evidence that this action is mediated by protein kinase A. In GH3 cells, VIP caused a time- and concentration-dependent decrease in TRH-R mRNA. This VIP effect was simulated by 8-(4-chlorophenylthio)-cAMP, forskolin, cholera toxin and 1-methyl-3-isobutylxanthine. When cells were incubated with agents that elevate cAMP and TRH or phorbol 12-myristate 13-acetate, the decrease in TRH-R mRNA was greater than with either agent alone. When cells were pre-incubated with H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride], an inhibitor of protein kinases, the effects of VIP, TRH and phorbol 12-myristate 13-acetate were inhibited. We suggest that VIP, via protein kinase A, and TRH, via protein kinase C, dually regulate TRH-R mRNA.
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PMID:Evidence for dual regulation by protein kinases A and C of thyrotropin-releasing hormone receptor mRNA in GH3 cells. 165 32

Heterologous expression of the rat 5-HT1A receptor in stably transfected GH4C1 rat pituitary cells (clone GH4ZD10) and mouse Ltk- fibroblast cells (clone LZD-7) (Albert, P.R., Zhou, Q.-Y., VanTol, H.H.M., Bunzow, J.R., and Civelli, O. (1990) J. Biol. Chem. 265, 5825-5832) was used to characterize the cellular specificity of signal transduction by the 5-HT1A receptor. We demonstrate that the 5-HT1A receptor, acting via pertussis toxin-sensitive G proteins, can change its inhibitory signaling phenotype and become a stimulatory receptor, depending on the cell type, differentiation state, or intracellular milieu of the cell in which it is expressed. When expressed in pituitary GH4ZD10 cells, activation of 5-HT1A receptors decreased both basal and vasoactive intestinal peptide-enhanced cAMP accumulation and blocked (+/-)-Bay K8644-induced influx of calcium, inhibitory responses which are typical of neurons which endogenously express this receptor. Similarly, 5-hydroxytryptamine (5-HT) also inhibited adenylyl cyclase in fibroblast LZD-7 cells, reducing the forskolin-induced enhancement of cAMP levels by 50%, but did not alter basal cAMP levels. In contrast to GH4ZD10 cells, where 5-HT had no effect on basal or thyrotropin-releasing hormone-induced phosphatidylinositol turnover, 5-HT enhanced the accumulation of inositol phosphates and induced a biphasic increase in [Ca2+]i in LZD-7 cells. These dominant stimulatory actions of 5-HT, as well as the inhibitory effects, were absent in untransfected cells and displayed the potency and pharmacological specificity of the 5-HT1A receptor, indicating that the 5-HT1A subtype coupled to both inhibitory and stimulatory pathways in the fibroblast cell. The actions of 5-HT in GH and L cells were blocked by 24-h pretreatment with pertussis toxin, suggesting that inhibitory G proteins (Gi/G(o)) mediate both inhibitory and stimulatory signal transduction of the 5-HT1A receptor. However, the 5-HT-induced stimulatory pathway in fibroblasts was blocked selectively by acute (2-min) pretreatment with TPA, an activator of protein kinase C. This action of protein kinase C was potentiated by activation of protein kinase A, indicating that the expression of the stimulatory pathway of the 5-HT1A receptor in LZD-7 cells is modulated by second messengers.
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PMID:Cell-specific signaling of the 5-HT1A receptor. Modulation by protein kinases C and A. 166 Aug 81

Striatal neurons from the mouse brain embryo grown in primary culture express high levels of cyclic AMP (cAMP)-dependent protein kinase (PKA) activity. To study the modulation of PKA in intact neurons, a rapid method based on Zn(2+)-protein precipitation was developed. This strategy allowed analysis of the stimulation of PKA under conditions of intracellular cAMP concentration increases. Whereas increases up to 1 microM lead to an activation, large and sustained accumulations of cAMP result in a loss of the enzyme activity. With 8-bromo-cAMP (8-Br-cAMP) at 100 microM, the PKA refractoriness occurs within 2 min. It is rapidly reversible because incubation of treated neurons in fresh medium leads to a complete recovery of PKA activity within 30 min. The decrease in assayable PKA does not involve an activation of phosphatases because the histone dephosphorylation rate is not affected by 8-Br-cAMP treatment. Finally, not only 8-Br-cAMP- but also forskolin- and vasoactive intestinal peptide-induced increases in intracellular cAMP concentration can lead to the PKA desensitization. Altogether, these data unravel a new mechanism of PKA regulation.
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PMID:Cyclic AMP accumulation induces a rapid desensitization of the cyclic AMP-dependent protein kinase in mouse striatal neurons. 171 55

The regulation of intestinal peptide-YY (PYY) synthesis and secretion has not been well studied. We have used fetal rat intestinal cells in culture to examine the intra- and extracellular factors controlling the production of PYY. Immunohistochemical analysis demonstrated a distinct population of cells containing immunoreactive PYY (IR-PYY). When examined by HPLC, the IR-PYY stored and secreted by fetal rat intestinal cell cultures eluted as a single moiety with the same elution time as synthetic rat PYY. Pro-PYY mRNA transcript levels and secretion of IR-PYY into the cell medium were increased by activation of protein kinase-A with either a long-acting cAMP analog or forskolin. In contrast, IR-PYY secretion only was stimulated in a synergistic fashion through calcium- and protein kinase-C-dependent pathways (stimulated with A23187 and phorbol myristate acetate, respectively). The intestinal endocrine peptide, gastric inhibitory peptide, and the neurocrine peptide, gastrin-releasing peptide, were found to stimulate IR-PYY secretion in a dose-dependent fashion, with significant effects observed at concentrations as low as 10(-8) and 10(-12) M, respectively (P less than 0.05-0.001). Cholecystokinin and vasoactive intestinal peptide were without effect on IR-PYY secretion at doses of 10(-12)-10(-6) M. The fatty acid sodium oleate and the cholinergic agonist bethanechol were also found to stimulate IR-PYY secretion, each at a concentration of 10(-4) M (P less than 0.001). The results of the present study indicate that the synthesis and secretion of PYY by the rat intestine is under the regulatory control of a wide variety of extracellular agents, mediated by several intracellular signalling pathways.
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PMID:Regulation of peptide-YY synthesis and secretion in fetal rat intestinal cultures. 172 93

In the present study the effects of stimulus deprivation on vasoactive intestinal peptide (VIP)- and alpha 1-adrenergically mediated amplification of VIP-stimulated cAMP and cGMP accumulation were examined. Dispersed pinealocytes were prepared from either Sprague-Dawley rats maintained for 2 weeks in a normal lighting schedule providing 14 h of light/day (LD cells) or from animals maintained in constant lighting (LL cells). LL treatment enhanced the VIP-stimulated cAMP response up to 2-fold, while reducing the peak VIP-stimulated cGMP by 70%. In LL cells, phenylephrine potentiated the VIP-stimulated cAMP response, but did not potentiate the VIP-stimulated cGMP response. Potentiation of the cAMP response to VIP can be produced in LD cells by treatment with agents that elevate intracellular Ca2+ (depolarizing concentrations of K+ or A23187) or an activator of protein kinase-C [14 beta-phorbol 12-myristate 13-acetate (PMA)]. LL treatment abolished the potentiating effects of K+ or A23187 on cAMP and cGMP responses in VIP-treated cells. In contrast, LL treatment augmented the PMA potentiation of VIP-stimulated cAMP response. The potentiation effects of PMA and K+ on the cGMP response in VIP-treated cells, however, were suppressed by LL treatment. To further investigate the involvement of postreceptor mechanisms, forskolin was used to stimulate pineal cAMP and cGMP accumulation. LL treatment had similar effects on the forskolin-stimulated cyclic nucleotide responses, with one exception. Depolarizing concentrations of K+ potentiated the forskolin-stimulated cAMP response while having no effect on the VIP-stimulated cAMP responses. These findings suggest that LL treatment results in a larger VIP-stimulated cAMP response, while its effect on the cGMP response is inhibitory. LL treatment appears to inhibit a step distal to elevation of intracellular Ca2+ which is of importance to the alpha 1-adrenergic potentiation of VIP-stimulated cAMP and cGMP responses.
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PMID:See-saw signal processing: reciprocal effects of stimulus deprivation on vasoactive intestinal peptide-stimulated adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate accumulation in rat pinealocytes. 184 90

Transcription of the human vasoactive intestinal peptide (VIP) gene is regulated by both cyclic AMP and phorbol esters. A 17-nucleotide enhancer element within the human VIP gene mediates transcriptional activation by both phorbol esters and forskolin. Mutations of this element decrease responses to both agents, suggesting that the trans-acting proteins that mediate both modes of transcriptional regulation have similar DNA-binding characteristics. The response of the VIP enhancer element to forskolin, but not to 12-O-tetradecanoylphorbol-13-acetate, was attenuated by treatment with a recombinant inhibitor of the cAMP-dependent protein kinase, suggesting that the cAMP-dependent protein kinase and protein kinase C second messenger pathways that converge on this single enhancer element are distinct. The transcriptional activator cAMP-responsive element-binding (CREB) proteins and the c-fos.c-Jun complex interact with the VIP enhancer. The dual second messenger responses of the VIP gene may result from the interaction of this second messenger enhancer with different transcriptional activator proteins.
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PMID:Cyclic AMP- and phorbol ester-induced transcriptional activation are mediated by the same enhancer element in the human vasoactive intestinal peptide gene. 184 91

ARPP-21 (cAMP-regulated phosphoprotein, Mr = 21,000 as determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate), a phosphoprotein substrate for cAMP-dependent protein kinase, is unevenly distributed in adult rat brain. Using immunoblotting and phosphorylation in vitro followed by immunoprecipitation, ARPP-21 was found to be enriched in caudate-putamen, substantia nigra, nucleus accumbens and olfactory tubercle. Intermediate levels were found in cerebral cortex and hippocampus. ARPP-21 was very low in most other brain areas and was not detected in any of the peripheral tissues studied. Following unilateral lesion of the caudate-putamen with quinolinic acid, a marked decrease in the levels of ARPP-21 was observed in both the lesioned caudate-putamen (-75%) and the ipsilateral substantia nigra (-70%) compared with the unlesioned side. This result demonstrates the enrichment of ARPP-21 in striatonigral neurons. In slices of caudate-putamen, substantia nigra or cerebral cortex incubated in vitro, the phosphorylation of ARPP-21 was enhanced by 8-Br-cAMP, a stable analog of cAMP. In striatal slices, forskolin, a compound which stimulates adenylate cyclase directly, enhanced the phosphorylation of ARPP-21 with an EC50 of 0.5 microM. In conclusion, ARPP-21 is a neuron-specific phosphoprotein enriched in specific brain areas which are known to receive a rich dopaminergic innervation and to contain high levels of D1 dopamine receptors. The phosphorylation of ARPP-21 is likely to mediate some of the intracellular effects of neurotransmitters which stimulate adenylate cyclase in these regions, in particular dopamine and vasoactive intestinal peptide.
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PMID:ARPP-21, a cAMP-regulated phosphoprotein enriched in dopamine-innervated brain regions: tissue distribution and regulation of phosphorylation in rat brain. 196 23

Two novel polypeptides known as pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) and a shorter form of the peptide corresponding to the N-terminal 27 residues (PACAP27) were isolated from ovine hypothalamus. The N-terminal 28 residues of PACAP show 68% homology with vasoactive intestinal peptide (VIP). VIP has been reported to have specific binding sites in lymphocytes and inhibit mitogen-stimulated lymphocyte proliferation through a receptor-mediated stimulation of cAMP-dependent protein kinase. Using concanavalin A-induced proliferation of murine splenocytes as a model system, we now report that both PACAP38 and PACAP 27 can inhibit the proliferation of these cells in the same dose-dependent manner as VIP. The minimal effective concentration of the PACAPs was 10(-10)-10(-9) M. However, neither PACAP affected lipopolysaccharide-induced proliferation of murine splenocytes. The binding of [125I]PACAP27 to these splenocytes was rapid, time dependent, reversible, and proportional to the numbers of murine splenocytes. Scatchard analysis of displacement of the bound tracer by unlabeled PACAP27 indicated the existence of two classes of binding sites. The dissociation constant (Kd) was 0.86 +/- 0.24 nM and the maximal binding capacity (Bmax) was 1.13 +/- 0.39 fmol/10(6) cells for the high affinity binding site. The low affinity binding site had a Kd of 0.13 +/- 0.03 microM with a Bmax of 73.5 +/- 9.5 fmol/10(6) cells. PACAP38 and VIP displaced the binding of [125I]PACAP27 in the same manner as PACAP27 and Scatchard analyses indicated the presence of two classes of binding sites with Kd and Bmax similar to those for PACAP27. Furthermore, when [125I]VIP was used as a radiolabeled ligand, PACAP27 and PACAP38 displaced the [125I]VIP binding to the same degree as unlabeled VIP. Scatchard analysis indicated that there was no significant difference of the Kd or Bmax between PACAP and VIP. Taken together, these data suggest that PACAPs bind to a site similar or identical to that used by VIP which inhibit the proliferation of murine splenocytes induced by concanavalin A.
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PMID:Inhibition of mitogen-stimulated proliferation of murine splenocytes by a novel neuropeptide, pituitary adenylate cyclase activating polypeptide: a comparative study with vasoactive intestinal peptide. 198 59


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