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)

The role of intracellular cAMP and protein kinase A in dopamine-induced inhibition of dopamine neurons and the attenuation of this inhibition by neurotensin were studied in rat midbrain slices. Spontaneous activity of dopamine cells was recorded extracellularly from both the ventral tegmental area and the substantia nigra. Perfusion of the slices with 8-bromo-cAMP and forskolin significantly attenuated dopamine-induced inhibition, but neither blocked the inhibition completely. Neither SQ22536, an inhibitor of adenylate cyclase, nor H8, an inhibitor of protein kinase A, mimicked the inhibitory effect of dopamine on dopamine neurons, although they potentiated dopamine's effect. These results indicate that dopamine-induced inhibition of dopamine neurons can be affected by intracellular cAMP levels, but is unlikely to be mediated solely by inhibition of adenylate cyclase. The similarities between the effects of neurotensin and those of 8-bromo-cAMP and forskolin suggest that intracellular cAMP may be involved in the actions of neurotensin. This suggestion is supported by our findings that isobutyl-methylxanthine (an inhibitor of phosphodiesterases) potentiated the effect of neurotensin and SQ22536 and H8 antagonized it. Phorbol-12,13-dibutyrate (an activator of protein kinase C) did not mimic the effect of neurotensin, and H7 (an inhibitor of protein kinase C) did not reduce the effect, suggesting that protein kinase C is unlikely to be involved in the modulatory effect of neurotensin.
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PMID:Roles of intracellular cAMP and protein kinase A in the actions of dopamine and neurotensin on midbrain dopamine neurons. 131 60

The purpose of the present study was to determine whether neurotensin acts within the arcuate nucleus/median eminence to activate tyrosine hydroxylase (TH) within tuberoinfundibular dopamine neurons. The role of Ca2+/phospholipid-dependent protein kinase (protein kinase-C) in the regulation of TH and its involvement in the neurotensin-induced activation of TH within tuberoinfundibular dopamine (TIDA) neurons also was investigated. The activity of TH within TIDA neurons was assessed by quantification of the formation of 3,4-dihydroxyphenylalanine in the arcuate nucleus/median eminence after inhibition of 3,4-dihydroxyphenylalanine decarboxylase. Neurotensin (0.1-10 nM) increased the activity of TH within the arcuate nucleus/median eminence under in vitro conditions by approximately 80%. The activity of TH in the arcuate nucleus/median eminence also was increased approximately 55% by the phorbol ester 12-O-tetradecanoyl(phorbol-13-acetate) (1-100 nM), which activates protein kinase-C. Sphingosine (10 microM), an inhibitor of protein kinase-C, attenuated the activation of TH within TIDA neurons that was induced by both 12-O-tetradecanoyl(phorbol-13-acetate) and neurotensin. Sphingosine alone did not alter the activity of TH, nor did it alter the (Bu)2cAMP-induced activation of TH in the arcuate nucleus/median eminence. It is concluded that neurotensin acts directly within the arcuate nucleus/median eminence to activate TIDA neurons. Furthermore, it is suggested that the activity of TH within these neurons is enhanced after the activation of protein kinase-C and that protein kinase-C may mediate the neurotensin-induced activation of TH within these hypothalamic dopamine neurons.
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PMID:Evidence for protein kinase-C mediation of the neurotensin-induced activation of tyrosine hydroxylase in tuberoinfundibular dopaminergic neurons. 135 1

The pattern of expression of at least four neuropeptides contained in adrenomedullary chromaffin cells is altered by exposure to the cytokines interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF alpha), alone or in combination with stimulation of other second messenger pathways. Vasoactive intestinal polypeptide (VIP) was elevated 2- to 3-fold by 1 nM IL-1 alpha within 48 h of exposure, while neurotensin and substance P synthesis were unaffected, and met-enkephalin levels were decreased 25-35%. Stimulation of VIP and substance P biosynthesis by forskolin was markedly enhanced by IL-1 alpha, while forskolin stimulation of enkephalin and neurotensin biosynthesis was unaffected. IL-1 alpha amplified the effect of phorbol myristate acetate to increase the VIP content of chromaffin cells, but antagonized phorbol ester-induced elevation of neurotensin levels. TNF alpha also demonstrated a neuropeptide-specific pattern of modulation of second-messenger effects on chromaffin cell neuropeptide levels similar to those seen with IL-1 alpha. The neuroendocrine actions of IL-1 alpha described above, unlike IL-1 action in the immune system, do not appear to be mediated through IL-2 as this cytokine did not affect VIP or enkephalin expression in the presence or absence of protein kinase stimulation. Neither IL-1 alpha nor TNF alpha affected the calcium-coupled stimulation of neuropeptide secretion and biosynthesis that occurs in response to cell depolarization in these and other neuroendocrine cells in vitro and in vivo. These data provide a functional demonstration of IL-1 and TNF receptors in chromaffin cell cultures and suggest a physiological role for cytokine production in the adrenal medulla. Since both the magnitude and direction of neuropeptide synthesis modulation by IL-1 alpha and TNF alpha are highly peptide-specific, it appears that these cytokines do not merely augment second messenger pathways that affect neuropeptide synthesis, but potentially regulate the activity of factors controlling the pattern of neuropeptide gene expression in chromaffin cells.
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PMID:Interleukin-1 alpha and tumor necrosis factor-alpha differentially regulate enkephalin, vasoactive intestinal polypeptide, neurotensin, and substance P biosynthesis in chromaffin cells. 137 39

The adrenomedullary content of neurotensin and substance P was examined 1, 6, and 12 days after hypoglycemic shock. The neurotensin content was increased 60-fold within 24 h and remained elevated for up to 12 days, whereas the substance P content was increased approximately sevenfold within 24 h of insulin treatment and returned to control levels by 12 days poststimulation. Because protein kinase A, protein kinase C, and calcium influx in the rat adrenal medulla are all stimulated following splanchnic nerve stimulation, the differential regulation of neurotensin and substance P biosynthesis following stimulation of these three pathways was examined in bovine chromaffin cells in vitro. Neurotensin levels were up-regulated by elevated potassium, forskolin, and phorbol ester in bovine chromaffin cells. Substance P levels were up-regulated by elevated potassium and forskolin but not by phorbol ester treatment. When chromaffin cells were treated with phorbol ester in combination with forskolin, neurotensin levels were increased in a synergistic fashion, whereas phorbol ester antagonized the forskolin-induced elevation of substance P levels. Earlier, it was reported that galanin biosynthesis, like neurotensin biosynthesis, is upregulated by depolarization, phorbol ester stimulation, and forskolin treatment in chromaffin cells in vitro. Here we report that galanin is also, like neurotensin, increased greater than 60-fold after stimulation of the rat adrenal medulla in vivo. Neuropeptide-specific combinatorial effects of stimulating the calcium, protein kinase A, and protein kinase C signaling pathways may underlie the quantitative differences between galanin and neurotensin compared with substance P up-regulation in rat adrenal medulla after splanchnic nerve stimulation in vivo.
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PMID:Transsynaptic regulation of galanin, neurotensin, and substance P in the adrenal medulla: combinatorial control by second-messenger signaling pathways. 137 91

Three effects of NT were observed on midbrain DA cells. The modulatory effect of NT, that is, the attenuation of DA-induced inhibition, has been most extensively examined. Studies indicate that this effect of NT was not simply due to a nonspecific excitation. NT selectively attenuated DA-induced inhibition without affecting either GABA-induced inhibition or glutamate-induced excitation of the same cells, and the attenuation of DA-induced inhibition could be observed at the doses at which the basal activity of DA cells was not changed by NT. The attenuation of DA-induced inhibition by NT is also unlikely to result from the formation of a DA-NT complex, since neuromedin N, which competes with NT for the same receptor but does not bind to DA, mimicked the effects, and neurotensin(1-11), which forms a complex with DA but is inactive in competing for NT receptors, did not. The similarities between the effects of NT and those of 8-bromo-cAMP and forskolin suggest that intracellular cAMP and protein kinase A may be involved. This suggestion was supported by the findings that IBMX (an inhibitor of phosphodiesterases) potentiated the effect of NT; and SQ22536 (an inhibitor of adenylate cyclase) and H8 (an inhibitor of protein kinase A) antagonized it. Phorbal-12,13-dibutyrate (an activator of protein kinase C) did not mimic the effect of neurotensin, and H7 (an inhibitor of protein kinase C) did not reduce the effect, suggesting that protein kinase C is unlikely to be involved in the modulatory effect of neurotensin. Experiments in vitro indicated that the excitatory effect of NT on DA cells occurred at higher concentrations (> 10 nM) than those needed for producing the modulatory effect. Its persistence during DA receptor blockade by sulpiride suggests that this effect was not entirely mediated by an attenuation of the inhibition induced by endogenously released DA. At even higher concentrations (> 100 nM), a sudden cessation of cell activity preceded by an increase in firing rate was observed. Whether this effect of NT was due to depolarization inactivation or a toxic effect of the peptide at high concentrations remains to be determined. In most other areas studied, the excitatory effect of NT was most commonly observed. In many areas, this excitatory effect was apparently a direct postsynaptic effect of NT. However, different mechanisms may be involved (see Table 1). For example, in some areas NT acted through a decrease in membrane conductance, while in others no change or an increase in the membrane conductance was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Actions of neurotensin: a review of the electrophysiological studies. 146 69

Neurotensin (NT) is an endogenous brain tridecapeptide for which high affinity binding sites exist in the central nervous system. We have investigated the effects of NT incubation with rat neostriatal slices on calcium/calmodulin (Ca/CaM)-dependent protein phosphorylation. Slices were incubated with NT (5 or 50 nM) for 3, 10, 16 or 30 min followed by in vitro phosphorylation, electrophoresis and autoradiography. NT significantly altered the phosphorylation of a 62 kDa protein which is likely the beta subunit of the Ca/CaM dependent protein kinase. These changes may reflect the ability of NT to influence calcium mediated signal transduction.
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PMID:Neurotensin effects on calcium/calmodulin-dependent protein phosphorylation in rat neostriatal slices. 165 Feb 80

Nerve growth factor (NGF) cooperates with glucocorticoids, activators of adenylate cyclase, and lithium to induce the expression of teh gene encoding the neuropeptides neurotensin and neuromedin N (NT/N gene) in PC 12 pheochromocytoma cells. High level expression requires simultaneous treatment with three or all four inducers. To examine the mechanism underlying this complex synergism, we have examined the effects of protein kinase inhibitors and other agents which influence intracellular signal transduction on NT/N gene expression. Two structurally similar bacterial alkaloids, staurosporine and K-252a, inhibit several protein kinases in vitro, including protein kinase C and cyclic nucleotide-dependent kinases. K-252a has been reported to specifically inhibit the effects of NGF on PC12 pheochromocytoma cells. Surprisingly, staurosporine in combination with other inducers markedly potentiated NT/N gene expression. In contrast, K-252a had no effect on NT/N gene expression when added simultaneously with other inducers. Expression of the NT/N gene was also potentiated by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate, which directly activates protein kinase C, and by bradykinin, which stimulates phosphatidylinositol turnover in PC12 cells, and these effects were not blocked by staurosporine. Staurosporine was generally more effective in stimulating NT/N gene expression when used in inducer combinations that did not include NGF. These results, taken together with recent evidence that staurosporine is also able to induce neurite outgrowth from PC12 cells, suggest that the effects of staurosporine and NGF may converge, in part, on a common intracellular target.
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PMID:A protein kinase inhibitor, staurosporine, mimics nerve growth factor induction of neurotensin/neuromedin N gene expression. 170 31

A clonal cell line (44-2C) which synthesizes and secretes somatostatin, neurotensin, calcitonin (CT), and CT gene-related peptide and transiently expresses c-fos was used to characterize the mechanism of action of basic fibroblast growth factor (bFGF). bFGF had two modes of action: 1) short term incubation of 44-2C cells with bFGF increased the cellular content of neurotensin, somatostatin, and CT; and 2) bFGF enhanced the response of the cells to rat hypothalamic GRF-mediated cAMP efflux. The long term action of bFGF was manifested by the permissive effect of the molecule. bFGF had a sustained effect on RNA synthesis, and pretreatment with bFGF for 24 h altered the time course of response of the cells to rat GRF. In this cell line the cellular action of bFGF was not mediated via protein kinase-C action. bFGF was not mitogenic in 44-2C cells. bFGF stimulated uridine incorporation without affecting thymidine incorporation. Results obtained with actinomycin-D and alpha-amanitin suggest that the above effects of bFGF can be correlated with increased RNA stability produced by bFGF.
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PMID:Fibroblast growth factor stabilizes ribonucleic acid and regulates differentiated functions in a multipeptide-secreting neuroendocrine cell line. 244 40

This report presents findings pertaining to the role of protein kinase-Cs in the release of PRL and liberation of arachidonate from PRL-secreting cells. In our experiments, protein kinase-C activators increased PRL release and arachidonate liberation from anterior pituitary cells and from the PRL-secreting cell line MMQ. In cells depleted of pituitary protein kinase-Cs by chronic exposure to protein kinase-C activators, such as phorbol dibutyrate or 4 beta-phorbol 12 beta-myristate 13 alpha-acetate, TRH, angiotensin-II, and neurotensin each increased PRL release and [3H]arachidonate liberation in a normal manner. In addition, the PRL-releasing activities of protein kinase-C activators and those of TRH appeared to be synergistic, an unexpected effect if these substances were functioning through the same intracellular pathways. It, therefore, appears that phorbol diester-sensitive protein kinase-Cs may not be involved in the increased secretion of PRL or liberation of arachidonate that is caused by TRH, angiotensin-II, or neurotensin.
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PMID:Evidence that phorbol diester-sensitive protein kinase-C(s) may not be directly involved in secretagogue-stimulated prolactin release and arachidonate liberation. 250 62

Although dopamine inhibits PRL release from the normal anterior pituitary lactotroph, a conclusive demonstration of the mechanisms involved in this response has been impeded by the presence of other cell types in the anterior pituitary. To circumvent this problem, we have isolated a clonal cell line, designated MMQ, from the 7315a rat pituitary tumor. The MMQ cell is an exemplary model for our use because it only secretes PRL. Our studies show that dopamine inhibits secretagogue-induced PRL release from these cells. In addition, dopamine decreases the intracellular cAMP concentration in MMQ cells that have been exposed to forskolin, cholera toxin, or vasoactive intestinal polypeptide, each a stimulator of cAMP generation. This inhibition is, in turn, reversed by the dopamine antagonist haloperidol and by pertussis toxin, an inactivator of the GTP-binding coupling protein. Dopamine also decreases the uptake and fractional efflux of 45Ca2+ by MMQ cells that have been exposed to the calcium channel activator maitotoxin. It seems, therefore, that dopamine decreases PRL release from MMQ cells at least in part by decreasing intracellular cAMP levels and calcium uptake. In additional experiments, we have found that MMQ cells are responsive to somatostatin, estrogen, progesterone, and acetylcholine, but not to TRH, angiotensin II, neurotensin, or bombesin. Furthermore, these cells possess a functional protein kinase-C system, as evidenced by the increase in PRL release and decrease in stimulated intracellular cAMP levels that occur in response to treatment with phorbol diesters. We suggest that the MMQ cell line will prove a useful model system for study of the biochemical effects of dopamine and other factors that modify PRL release.
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PMID:Characterization of the MMQ cell, a prolactin-secreting clonal cell line that is responsive to dopamine. 284 8


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