Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of galanin (GAL) on basal and phorbol-12,13-dibutyrate (PDBu) induced protein phosphorylation in rat ventral hippocampal miniprisms was investigated. GAL (0.5, 1 and 2 microM) inhibited PDBu stimulation in a concentration-dependent manner without altering basal protein phosphorylation. This inhibitory effect was prevented by the GAL antagonist galantide. GAL did not affect either the activity of protein kinase C (PKC) from rat brain or basal phosphorylation in ventral hippocampal hippogenates, suggesting that it did not directly modulate PKC activity. Depolarization of miniprisms from ventral hippocampi by 18 mM K+ prevented the effect of GAL on PDBu-induced phosphorylation. The results indicate that GAL indirectly regulates neuronal protein phosphorylation by a GAL receptor-mediated action.
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PMID:Galanin reduces PDBu-induced protein phosphorylation in rat ventral hippocampus. 137 70

Treatment of segments of ileum from 8-week streptozotocin-induced diabetic rats with phorbol 12,13-dibutyrate (PDBu) in vitro resulted in restoration of the diabetes-induced changes in the expression of enteric VIP- and galanin-like immunoreactive nerve fibres. The increase in fluorescence intensity and density of VIP- and galanin-like immunoreactivity observed in 8-week streptozotocin-treated rats was reduced to a near normal level after 40 min incubation of diabetic tissues in Krebs solution containing PDBu (100 nM). The tissue content of VIP was also affected (control = 2.1 +/- 0.31 pmol/cm; diabetic = 4.6 +/- 0.48 pmol/cm; diabetic + PDBu = 2.9 +/- 0.91 pmol/cm) after incubation with PDBu. The significance of these findings in relation to the possible role of protein kinase C in the regulation of expression and/or storage of these enteric neuropeptides in normal and diabetic states is discussed.
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PMID:Restoration of diabetes-induced changes in enteric nerves by phorbol 12,13-dibutyrate. 137 84

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

Enzymatically isolated rat gastric mucosal cells (0.25% G-cells) were separated by counterflow elutriation, yielding a fraction in which the G-cell content was relatively enriched to 1.4%. In this fraction, basal gastrin release (mean +/- SE) was 31.1 +/- 1.3 pg.10(6) cells-1.60 min-1 and was stimulated by 10(-8) M neuromedin C (222.3 +/- 18.1% of basal), 10(-4) M carbachol (227.5 +/- 25.9%), 10(-6) M 12-O-tetradecanoylphorbol-13-acetate (TPA) (196.3 +/- 14.7%), and 10(-3) M dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) (193.9 +/- 6.8%), respectively. The neuropeptide galanin was tested at 10(-10) to 10(-7) M. Galanin had no effect on basal gastrin release but reduced the responses to neuromedin C, carbachol, TPA, and DBcAMP. IC50 ranged between 1 X 10(-10) and 8.6 X 10(-10) M galanin. Although in the relatively enriched G-cell fraction D-cells were not detectable by immunocytochemistry, a low rate of somatostatin release was still measured by radio-immunoassay (5.3 +/- 0.5 pg.10(6) cells-1.60 min-1). However, galanin failed to increase this rate under basal conditions or in response to any of the stimulants tested. These results favor the assumption that galanin might exert a direct inhibitory effect on rat gastric G-cells. Galanin seems to interfere at an intracellular mechanism(s), which is induced by neuromedin C and carbachol and which is commonly activated by protein kinase C- and cAMP-mediated stimulation.
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PMID:Galanin inhibits gastrin release from isolated rat gastric G-cells. 169 87

The neuropeptide galanin (GAL) is widely distributed throughout the diffuse neuroendocrine system, and is coexpressed with acetylcholine, norepinephrine, prolactin, and a variety of other messenger substances in different cell types. Bovine chromaffin cells in primary culture synthesize and store GAL along with catecholamines, chromogranin A, and enkephalin peptides, as well as other neurosecretory products, and secrete all these molecules in response to nicotinic stimulation. The regulation of GAL biosynthesis and secretion were studied by measuring changes in messenger RNA (mRNA(GAL], and peptide immunoreactivity, 24-72 h after stimulation of secretion (40 mM potassium or 10 microM veratridine), or exposure to stimulators of protein kinase C (100 nM phorbol myristate acetate) and protein kinase A (25 microM forskolin). Depolarization-induced stimulation of GAL biosynthesis, like that of enkephalin and other neuropeptides, was calcium dependent, suggesting that calcium generally mediates both exocytotic release and new peptide synthesis thus coordinating maintenance of neuropeptide levels in chromaffin cells. GAL and mRNA(GAL) were also upregulated by stimulation of protein kinase A with forskolin. Treatment with PMA increased GAL and mRNA(GAL) to an even greater extent than depolarization. Thus GAL expression can be regulated by three distinct signal transduction systems in chromaffin cells: depolarization-stimulated calcium influx, activation of protein kinase C and activation of protein kinase A, which in addition differentially up- and down-regulate the expression of several other neurosecretory proteins and peptides resulting in different patterns of GAL/neuropeptide coexistence in bovine chromaffin cells. GAL coexistence with diverse neuroendocrine substances may reflect the relative activity of these three signalling systems in other neuroendocrine cell types as well.
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PMID:Galanin gene expression in chromaffin cells is controlled by calcium and protein kinase signaling pathways. 170 Nov 35

Addition of the neuropeptide galanin to small cell lung cancer (SCLC) cells loaded with the fluorescent Ca2+ indicator fura-2-tetraacetoxymethylester causes a rapid and transient increase in the intracellular concentration of Ca2+ ([Ca2+]i) followed by homologous desensitization. Galanin increased [Ca2+]i in a concentration-dependent fashion with half-maximum effect (EC50) at 20-22 nM in H69 and H510 SCLC cells. Galanin mobilized Ca2+ from intracellular stores since its effects on [Ca2+]i were not blocked by chelation of extracellular Ca2+. Pretreatment with pertussis toxin (200 ng/ml for 4 h) did not prevent galanin-induced Ca2+ mobilization. In contrast, direct activation of protein kinase C with phorbol esters attenuated the Ca2+ response induced by galanin. The effects of galanin could be dissociated from changes in membrane potential: galanin did not increase membrane potential in SCLC cells loaded with bis(1,3-diethyltiobarbiturate)-trimethineoxonol and induced Ca2+ mobilization in depolarized SCLC cells, i.e., in cells suspended in a solution containing 145 mM K+ instead of Na+. Galanin also caused an increase in the formation of inositol phosphates in a time- and dose-dependent manner (EC50 10 nM). A rapid increase in the inositol trisphosphate fraction was followed by a slower increase in the inositol monophosphate fraction. Galanin stimulated clonal growth of both H69 and H510 cells in semisolid (agarose-containing) medium. This growth-promoting effect was sharply dependent on galanin concentration (EC50 20 nM) and markedly inhibited by [Arg6,D-Trp7,9,MePhe8]substance P, a recently identified broad spectrum neuropeptide antagonist. The results show for the first time that galanin receptors are coupled to inositol phosphate and [Ca2+]i responses in SCLC cells and, in particular, that this neuropeptide can act as a direct growth factor for these human cancer cells.
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PMID:Galanin stimulates Ca2+ mobilization, inositol phosphate accumulation, and clonal growth in small cell lung cancer cells. 170 78

The mechanism by which the neuropeptide galanin inhibits insulin secretion in normal islets is not yet fully elucidated. Isolated rat or mouse islets were perifused in a medium containing glucose (8.3 mM) and galanin (10(-6) M) or the sulphonamide diazoxide (400 microM). In rat islets prelabelled with 86Rb+ or 45Ca2+, galanin inhibited glucose-induced insulin secretion at the same time as increasing 86Rb+ efflux and reducing 45Ca2+ efflux. The diazoxide-induced 86Rb+ efflux was not affected by galanin, indicating that galanin activates ATP-regulated K+ channels in rat islets. In mouse islets prelabelled with 86Rb+, galanin (10(-6) M) decreased 86Rb+ efflux. These results suggest that galanin inhibits insulin release in isolated islets by increasing K+ and decreasing Ca2+ permeability. The increased K+ permeability, which is probably regulated differently in rat and mouse islets, is followed by a reduced Ca2+ influx, possibly through voltage-dependent Ca2+ channels. In addition, during a 60-min incubation with isolated islets, galanin inhibited insulin secretion induced by forskolin (1 microM), dibutyryl cyclic AMP (1 mM), or TPA (12-O-tetradecanoylphorbol-13-acetate; 0.1 microM). Galanin also reduced the content of cyclic AMP in islets stimulated by 16.7 mM glucose. We therefore conclude that the inhibitory action of galanin on insulin secretion in normal islets includes increasing K+ permeability as well as interference with the activation of adenylate cyclase and the activity of protein kinase C and cyclic AMP.
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PMID:Studies on the mechanism by which galanin inhibits insulin secretion in islets. 172 64

The ability of bombesin to stimulate acetylcholine release from guinea pig myenteric plexus neurons was studied using a primary neuronal culture system. Bombesin caused dose-dependent increases in [3H]-acetylcholine (ACh) release from guinea pig myenteric plexus neurons. ACh release in response to 0.5 mM bombesin (160 +/- 12% of control) was blocked by exposure to a calcium-free medium (116 +/- 13%) by nifedipine (101 +/- 11%) and by omega conotoxin (107 +/- 10%). Bombesin-stimulated ACh release was inhibited the protein kinase C inhibitor, H7, but was not affected by inhibitors of the cAMP signaling pathway. Interactions with inhibitory neuropeptides was implied by sensitivity of bombesin-stimulated ACh release to neuropeptide Y and galanin. The findings suggest that bombesin activation of protein kinase C in myenteric neurons results in increased acetylcholine release.
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PMID:Bombesin-stimulated acetylcholine release from myenteric plexus neurons. 836 Nov 63

The regulation of clonal rat insulinoma (RINm5F) cell proliferation and hormone accumulation was investigated with the aim of identifying putative compounds capable of inducing differentiation, i.e. decreased growth and increased insulin accumulation, by the tumor cells. In particular, interest was focused on the role of a number of peptides as well as pharmacological probes modulating various signal transduction systems and which have been shown to regulate normal beta-cell proliferation and insulin accumulation. Growth hormone stimulated insulin accumulation and inhibited DNA synthesis, whereas galanin and insulin-like growth factor I caused a moderate suppression of insulin accumulation but did not affect proliferation, while epidermal growth factor, transforming growth factor beta, platelet-derived growth factor, acidic and basic fibroblast growth factor, bradykinin and somatostatin were virtually inactive on all parameters tested. Exogenous prostaglandins E2 and F1 alpha were inactive, while the cycloxygenase inhibitor indomethacin slightly suppressed insulin accumulation. The cytokine IL-1 beta caused a significant decrease in both beta-cell mitogenesis and insulin accumulation, effects that were mediated through nitric oxide generation. The vitamin A derivative retinyl acetate slightly inhibited serum-stimulated DNA synthesis, but did not affect insulin accumulation. The vitamin E alpha-tocopherol significantly enhanced insulin release but did not affect mitogenesis. By contrast, gamma-tocopherol was inactive on both these parameters. The alpha-adrenergic agonist clonidine evoked a slight inhibition of serum-stimulated DNA synthesis, without influencing insulin accumulation, whereas phenylephrine did not affect any of these parameters. Carbamylcholine increased insulin accumulation, but not cell proliferation, whereas the adenylyl cyclase activator forskolin suppressed mitogenesis but did not affect insulin accumulation. Inhibition of protein kinase C with staurosporine or prolonged treatment with phorbol ester suppressed DNA synthesis, as did the tyrosine kinase inhibitor genistein. Stimulating Ca2+ influx by closing ATP-dependent K+ channels with glibenclamide enhanced DNA synthesis, while opening of these channels with diazoxide suppressed cell growth. Conversely, preventing Ca2+ influx by the Ca2+ channel antagonist D-600, chelating intracellular Ca2+ by fura-2 AM or inhibiting the Ca2+/calmodulin-dependent protein kinase by calmidazol resulted in a decreased DNA synthesis. On the other hand, uncontrolled influx or mobilization of Ca2+ by ionomycin or thapsigargin resulted in an arrested DNA synthesis. The present paper shows that RINm5F insulinoma cell proliferation and insulin accumulation can be modulated by various peptidergic and pharmacological agents regulating certain signal transduction pathways. However, mitogenesis in the insulinoma cells seemingly is controlled in a vastly different manner in comparison to that in normal beta-cells. The most spectacular finding in this screening study, i.e. that growth hormone, contrarily to its effect on normal beta-cells, suppresses insulinoma cell growth, merits further elucidation of the underlying mechanisms. Possibly the hormone might become of utility in a clinical setting in the treatment of patients with insulin-producing tumors.
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PMID:Regulation of insulinoma cell proliferation and insulin accumulation by peptides and second messengers. 880 83

The neuropeptides galanin and pituitary adenylate cyclase-activating peptide (PACAP) have been implicated in the physiological regulation of lactotroph function. Using the 235-1 clonal lactotroph rat cell line we have studied the signalling pathways mediating the secretory and mitogenic responses to galanin and PACAP. Both peptides stimulated prolactin release to a similar maximal extent. PACAP (100 nM) stimulated an increase in the proliferation rate of 235-1 cells, but was significantly less effective than 100 nM galanin (161.8 +/- 2.3% vs 296.1 +/- 9.1% of control). PACAP stimulated cAMP accumulation with an ED50 of 3.2 nM, and a maximal effect of almost two-fold at a concentration of 100 nM. Galanin depleted cAMP, by 30% at a concentration of 100 nM. The aminosteroid phospholipase C (PLC) inhibitor U-73122 virtually abolished maximal peptide stimulated prolactin release. Depletion of inositol phosphates or downregulation of protein kinase C reduced maximal peptide stimulated prolactin release from about 260% to about 160% of unstimulated release. Both peptides at a concentration of 100 nM caused a sustained increase in intracellular calcium when incubated with cells for 30 min. These results demonstrate that both peptides stimulate prolactin release and the proliferation rate of 235-1 cells. The most important signalling pathway for prolactin release activated by both peptides is via PLC, although they also regulate cAMP levels, which are increased by PACAP and decreased by galanin. Despite maximal peptide stimulated prolactin release being equal, galanin has a greater mitogenic effect on 235-1 cells than PACAP, raising the possibility that it activates an additional mitogenic signalling pathway.
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PMID:Signalling pathways mediating secretory and mitogenic responses to galanin and pituitary adenylate cyclase-activating polypeptide in the 235-1 clonal rat lactotroph cell line. 880 76


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