UNIPROT:P01275 - FACTA Search

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Query: UNIPROT:P01275 (glucagon)
26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, it was shown that lipoprotein lipase (LPL) was produced in neonatal but not in adult rat liver. In an attempt to further define the mechanism involved in liver LPL expression, we identified a neonatal mouse hepatoma cell line, BWTG3, capable of producing LPL. The regulation of LPL expression by various extracellular stimuli was investigated in this cell line. Progesterone caused a rise in LPL production by BWTG3 cells. Other hormones tested, such as insulin, glucagon, adrenalin, testosterone, and thyroid hormone, had no effect on LPL production. The effects of progesterone on LPL production showed slow kinetics reaching a maximum 24 h after addition. Cotransfection of a progesterone receptor expression vector with a 5'-LPL-CAT reporter construct resulted in an induction of CAT activity, suggesting that the increase in LPL accumulation after progesterone was linked to transcriptional induction of the LPL gene. Stimuli causing an elevation of protein kinase A activity in the cells also increased LPL production. Three agents capable of elevating intracellular cAMP levels, i.e., forskolin, dBcAMP, and choleratoxin, caused an elevation of LPL production. The increase in LPL activity caused by forskolin and choleratoxin was paralleled by an elevation of LPL mRNA levels, while dBcAMP only induced a small elevation of LPL mRNA levels. The increase in LPL production was shown to be linked to the stimulation of the PKA signal transduction pathway and was apparently transmitted via the transcription factor CREB. No effect of the stimulation of protein kinase C or calcium/calmodulin-dependent kinase on LPL production was detected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipoprotein lipase expression in undifferentiated hepatoma cells is regulated by progesterone and protein kinase A. 132 33

Using several novel in vitro culture systems, we have examined the tissue-specific regulation of the proglucagon-derived peptides, at the levels of proglucagon gene expression and pGdp synthesis and secretion. Our studies indicate that proglucagon gene expression in intenstine, hypothalamus and pancreas is under the regulatory control of protein kinase A- but not a protein kinase C-dependent pathway. PKA and PKC stimulate secretion of the intestinal pGdp's, whereas only PKA stimulates secretion of the hypothalamic peptides. Pancreatic glucagon secretion in response to PKA is subject to further modulation by prevailing glucose concentrations. This diversity in intracellular regulation of the pGdp's may account for some of the tissue-specific differences in synthesis and secretion of the pGdp's that we have observed in diabetes and during development.
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PMID:Proglucagon-derived peptides in the neuroendocrine system. 192 80

The glycogenolytic potency of adenosine and ATP was studied in adult rat hepatocytes and compared with the action of glucagon and noradrenaline. In cells cultured for 48 h, adenosine and ATP as well as their analogues 2-chloroadenosine, phenylisopropyladenosine, N-ethylcarboxamidoadenosine and beta-gamma-methylene-substituted ATP (p[CH2]ppA) increased glycogen phosphorylase alpha to levels indistinguishable from those obtained by the addition of glucagon or noradrenaline. The P1 receptor antagonist 8-phenyltheophylline abolished the activation of phosphorylase by adenosine and by p[CH2]ppA, but not that by ATP. Protein kinase A was activated by p[CH2]ppA and ATP via their breakdown to adenosine. [14C]Glucose production from glycogen was stimulated only 3-fold by ATP and adenosine, compared with a 7-fold increase produced by the hormones. Stimulation of glucose production by glucagon or noradrenaline was almost completely abolished by ATP or adenosine, with half-maximal effects at around 10 microM. The non-degradable adenosine analogues were equipotent with glucagon with respect to stimulation of glucose production, and their action was also inhibited by adenosine. ATP and p[CH2]ppA, which were both degraded to adenosine, showed comparable metabolic effects, whereas the alpha, beta-methylene analogue was without biological action and also was not degraded to adenosine. In the presence of the adenosine transport inhibitor nitrobenzyl thioinosine (NBTI), adenosine exerted an increased glycogenolytic potency, reaching 80% of the maximal stimulation obtained by glucagon. The glucagon-antagonistic effect of adenosine could be completely abolished by NBTI, but was not affected by phenyltheophylline. It is concluded that, in the hepatocyte culture system, adenosine and ATP decrease the catalytic efficiency of phosphorylase alpha through signals arising from their uptake into the cell.
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PMID:Stimulation of glucose production from glycogen by glucagon, noradrenaline and non-degradable adenosine analogues is counteracted by adenosine and ATP in cultured rat hepatocytes. 217 59

In previous studies it was shown that bovine GH (bGH) and glucagon, when individually added to primary rat hepatocyte cultures, modestly stimulated IGF-I mRNA levels 1.8- to 2.5-fold, but when combined, synergized to stimulate IGF-I mRNA levels by 10- to 12-fold. In the present study we have explored further the mechanism of this effect in primary rat hepatocyte cultures. Like glucagon, the addition of 3-isobutyl-1-methylxanthine (100 microM) or (Bu)2cAMP (150 microM) augmented IGF-I mRNA levels 1.8- to 2.0-fold, but when combined with bGH (50 ng/ml), they augmented levels up to 12-fold. The half-life of IGF-I mRNA, determined by incubating hepatocytes with actinomycin-D was 12 h. Although bGH did not affect the decay rate, glucagon (100 ng/ml) or (Bu)2cAMP (100 microM) reduced the rate of loss by about 70%. 4 beta-Phorbol 12 beta-myristate 13 alpha-acetate minimally stimulated IGF-I mRNA levels 1.2- to 1.4-fold, but displayed no synergism when added with bGH, glucagon, or (Bu)2cAMP. The stimulatory effect of bGH plus glucagon was inhibited 80% after preincubation with 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (10 microM) for 24 h. The addition of staurosporine, sphingosine, or H-7 [1-(5-isoquinolinyl sulfonyl)2-methyl piperazine] inhibited the stimulatory effect of bGH plus glucagon on hepatocyte IGF-I mRNA by 80%, 90%, and 85%, respectively. Preincubation with cycloheximide (10 micrograms/ml) blocked the synergistic effect of bGH plus either glucagon or (Bu)2cAMP by 65-80%. The effect of glucagon, mediated via the activation of adenylate cyclase, involves in part the posttranscriptional stabilization of IGF-I mRNA levels. The effect of GH, mediated in part by the activation of protein kinase-C, appears to be at the level of transcription. The synergistic augmentation of hepatocyte IGF-I mRNA levels by GH and glucagon involves the activation of PKA and PKC, but also appears to require the synthesis of one or more protein(s).
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PMID:The augmentation of insulin-like growth factor-I messenger ribonucleic acid in cultured rat hepatocytes: activation of protein kinase-A and -C is necessary, but not sufficient. 750 34

In previous studies it was shown that bovine GH (bGH) suppressed and glucagon stimulated the level of 24- and 30- to 34-kilodalton insulin-like growth factor-binding proteins (IGFBPs) in the media of cultured rat hepatocytes. In the present study we have evaluated the regulation of IGFBP-1 gene expression in primary rat hepatocyte cultures. Glucagon produced a dose-dependent stimulation of hepatocyte IGFBP-1 messenger RNA (mRNA), attaining levels 2- to 6-fold greater than control at a glucagon concentration of 100 ng/ml. GH inhibited the accumulation of IGFBP-1 mRNA in a dose-dependent manner producing, 40-70% inhibition at 50 ng/ml. The effect of glucagon was comparable to and additive with dexamethasone (1 microM). The addition of 3-isobutyl-1-methylxanthine (100 microM) and (Bu)2cAMP (100 microM) augmented IGFBP-1 mRNA levels 5- to 6-fold. 4 beta-Phorbol 12 beta-myristate 13 alpha-acetate (300 nM) was found to inhibit IGFBP-1 mRNA levels by 40-50%. The inhibitory effect of bGH on IGFBP-1 mRNA levels was abolished after preincubation with 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (10 microM) for 24 h, whereas glucagon's stimulatory effect was unaffected. The addition of staurosporine (500 nM) and H-7 (1 mM) abolished the inhibitory effect of GH but also significantly inhibited the stimulatory effect of glucagon, a result consistent with these agents acting on both protein kinase C (PKC) and PKA. In the presence of 10 micrograms/ml cycloheximide, IGFBP-1 gene expression was superinduced by bGH, whereas the effect of glucagon was uninfluenced. Thus the inhibitory action of GH involves, in part, the activation of PKC. Glucagon's stimulatory effect seems to involve the activation of PKA. The inhibitory effect of bGH on IGFBP-1 gene expression may require the continuing synthesis of one or more labile protein(s).
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PMID:The regulation of insulin-like growth factor-binding protein 1 messenger ribonucleic acid in cultured rat hepatocytes: the roles of glucagon and growth hormone. 752 49

The mechanisms by which glucagon-like peptide 1(7-36)amide (GLP-1[7-36]amide) potentiates insulin secretion were investigated by measurements of whole-cell K+ and Ca2+ currents, membrane potential, the cytoplasmic Ca2+ concentration ([Ca2+]i) and exocytosis in mouse pancreatic B-cells. GLP-1(7-36)amide (10 nM) stimulated glucose-induced (10 mM) electrical activity in intact pancreatic islets. The effect was manifested as a 34% increase in the duration of the bursts of action potentials and a corresponding 28% shortening of the silent intervals. GLP-1(7-36)amide had no effect on the electrical activity at subthreshold glucose concentrations (< or = 6.5 mM). In cultured B-cells, GLP-1(7-36)amide produced a decrease of the whole-cell ATP-sensitive K+ (KATP) conductance remaining at 5 mM glucose by approximately 30%. This effect was associated with membrane depolarization and the initiation of electrical activity. GLP-1(7-36)amide produced a protein-kinase-A-(PKA-) and glucose-dependent fourfold potentiation of Ca(2+)-induced exocytosis whilst only increasing the Ca2+ current marginally. The stimulatory action of GLP-1(7-36)amide on exocytosis was mimicked by the pancreatic hormone glucagon and exendin-4, a GLP-1 receptor agonist. Whereas the stimulatory action of GLP-1(7-36)amide could be antagonized by exendin-(9-39), this peptide did not interfere with the ability of glucagon to stimulate exocytosis. We suggest that GLP-1(7-36)amide and glucagon stimulate insulin secretion by binding to distinct receptors. The GLP-1(7-36)amide-induced stimulation of electrical activity and Ca2+ influx can account for (maximally) a doubling of insulin secretion. The remainder of its stimulatory action results from a cAMP/PKA-dependent potentiation of Ca(2+)-dependent exocytosis exerted at a stage distal to the elevation of [Ca2+]i.
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PMID:Multisite regulation of insulin secretion by cAMP-increasing agonists: evidence that glucagon-like peptide 1 and glucagon act via distinct receptors. 924 14

We have monitored electrical activity, voltage-gated Ca2+ currents, and exocytosis in single rat glucagon-secreting pancreatic A-cells. The A-cells were electrically excitable and generated spontaneous Na+- and Ca2+-dependent action potentials. Under basal conditions, exocytosis was tightly linked to Ca2+ influx through omega-conotoxin-GVIA-sensitive (N-type) Ca2+ channels. Stimulation of the A-cells with adrenaline (via beta-adrenergic receptors) or forskolin produced a greater than fourfold PKA-dependent potentiation of depolarization-evoked exocytosis. This enhancement of exocytosis was due to a 50% enhancement of Ca2+ influx through L-type Ca2+ channels, an effect that accounted for <30% of the total stimulatory action. The remaining 70% of the stimulation was attributable to an acceleration of granule mobilization resulting in a fivefold increase in the number of readily releasable granules near the L-type Ca2+ channels.
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PMID:Adrenaline stimulates glucagon secretion in pancreatic A-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels. 927 50

Transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene is induced by glucagon, acting through cAMP and protein kinase A, and this induction is inhibited by insulin. Conflicting reports have suggested that insulin inhibits induction by cAMP by activating the Ras/mitogen-activated protein kinase (MAPK) pathway or by activating the phosphatidylinositol 3-kinase (PI3-kinase), but not MAPK, pathway. Insulin activated PI3-kinase phosphorylates lipids that activate protein kinase B (PKB) and Ca2+/diacylglycerol-insensitive forms of protein kinase C (PKC). We have assessed the roles of these pathways in insulin inhibition of cAMP/PKA-induced transcription of PEPCK by using dominant negative and dominant active forms of regulatory enzymes in the Ras/MAPK and PKB pathways and chemical inhibitors of PKC isoforms. Three independently acting inhibitory enzymes of the Ras/MAPK pathway, blocking SOS, Ras, and MAPK, had no effect upon insulin inhibition. However, dominant active Ras prevented induction of PEPCK and also stimulated transcription mediated by Elk, a MAPK target. Insulin did not stimulate Elk-mediated transcription, indicating that insulin did not functionally activate the Ras/MAPK pathway. Inhibitors of PI3-kinase, LY294002 and wortmannin, abolished insulin inhibition of PEPCK gene transcription. However, inhibitors of PKC and mutated forms of PKB, both of which are known downstream targets of PI3-kinase, had no effect upon insulin inhibition. Dominant negative forms of PKB did not interfere with insulin inhibition and a dominant active form of PKB did not prevent induction by PKA. Phorbol ester-mediated inhibition of PEPCK transcription was blocked by bisindole maleimide and by staurosporine, but insulin-mediated inhibition was unaffected. Thus, insulin inhibition of PKA-induced PEPCK expression does not require MAPK activation but does require activation of PI3-kinase, although this signal is not transmitted through the PKB or PKC pathways.
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PMID:Assessment of the roles of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase B, and protein kinase C in insulin inhibition of cAMP-induced phosphoenolpyruvate carboxykinase gene transcription. 966 48

Glucose, that Claude Bernard has demonstrated in 1850 to be synthesized and secreted by the liver, is an important regulator of gene transcription in all types of organisms. In vertebrates, it especially regulates transcription of metabolic genes in the liver and fat tissue, activating genes encoding enzymes and regulators of the glycolytic and lipogenic pathways. Working with the L-type pyruvate kinase gene we have found that in hepatocytes glucose-dependent gene regulation requires: Presence of the GLUT2 glucose transporter, necessary to allow for an effective depletion in glucose 6-phosphate (G-6P) under gluconeogenic conditions. Phosphorylation of glucose to G-6P assured either by insulin-dependent glucokinase or by another hexokinase isoform. Most likely, entry of G-6P in the pentose phosphate pathway. Modulation of a kinase/phosphatase cascade, in particular inhibition of the 5'AMP-activated protein kinase. Signalling through a glucose response complex assembled onto a glucose-response element (GIRE) located in regulatory regions of glucose-responsive genes. The activators USF belong to the complex, and are required for a normal gene activation by glucose, as evidenced from the phenotype of knock-out mice deficient in USF. The study of USF-defective knock-out mice suggest that USF could be involved in nutritional activation of a whole class of genes regulated by glucose, and not by insulin itself. In particular, lipogenic genes and the ob gene, encoding the leptin satiety hormone, are abnormally responsive to diet in USF-/- mice. The transactivation potential of USF would be modulated by a glucose sensor system implying the COUP-TFII transcription inhibitor. The main role of insulin in the glucose response of genes like the L-PK gene is to induce the glucokinase gene. Glucagon, through cyclic AMP, inhibits L-PK gene transcription mainly through activation of PKA. The PKA catalytic subunit could act by phosphorylating member(s) of the glucose-response complex, or of contiguous transcription factor, e.g. HNF4. In conclusion, through a pluridisciplinary approach ranging from Claude Bernard-derived biology to modern molecular biology, important progress have been made during the last years on the mechanisms of the regulation of gene transcription by glucose in vertebrates.
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PMID:[From the glycogenic function of the liver to gene regulation by glucose]. 987 95

Glucagon and the glucagon-like peptides regulate metabolic functions via signaling through a glucagon receptor subfamily of G protein-coupled receptors. Activation of glucagon-like peptide-2 receptor (GLP-2R) signaling maintains the integrity of the intestinal epithelial mucosa via regulation of crypt cell proliferation. Because GLP-2 decreases mortality and reduces intestinal apoptosis in rodents after experimental injury, we examined whether GLP-2R signaling directly modifies the cellular response to external injury. We show here that activation of GLP-2R signaling inhibits cycloheximide-induced apoptosis in baby hamster kidney fibroblasts expressing a transfected GLP-2 receptor. GLP-2 reduced DNA fragmentation and improved cell survival, in association with reduced activation of caspase-3 and decreased poly(ADP-ribose) polymerase cleavage and reduced caspase-8 and caspase-9-like activities. Both GLP-2 and forskolin reduced mitochondrial cytochrome c release and decreased the cycloheximide-induced cleavage of caspase-3 in the presence or absence of the PKA inhibitor H-89. Similarly, GLP-2 increased cell survival following cycloheximide in the presence of the kinase inhibitors PD98054 and LY294002. These findings provide evidence that signaling through G protein-coupled receptors of the glucagon superfamily is directly linked to regulation of apoptosis and suggest the existence of a cAMP-dependent protein kinase-, phosphatidylinositol 3-kinase-, and mitogen-activated protein kinase-independent pathway coupling GLP-2R signaling to caspase inhibition and cell survival.
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PMID:The glucagon-like peptide-2 receptor mediates direct inhibition of cellular apoptosis via a cAMP-dependent protein kinase-independent pathway. 1094 Mar 5

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