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)

In the absence of any exogenous substrates, glucagon (1 X 10(-9) M) stimulated 45Ca2+ efflux from perfused livers derived from fed rats but not in livers of 24-h-fasted animals. In livers of 24-h-fasted animals perfused under conditions which would decrease cellular NAD(P)H/NAD(P)+ ratio (pyruvate (2.0 mM) or acetoacetate (10.0 mM], glucagon (1 X 10(-9) M) did not stimulate 45Ca2+ efflux. Similarly, in livers of 24-h-fasted animals perfused with substrates which increase cellular NAD(P)H content (lactate (2.0 mM) or beta-hydroxybutyrate (10.0 mM], glucagon (1 X 10(-9) M) did not increase 45Ca2+ efflux. Glucagon (1 X 10(-9) M) elicited an increase in 45Ca2+ efflux from livers of 24-h-fasted animals, only when the livers were perfused with [lactate]/[pyruvate] and [beta-hydroxybutyrate]/[acetoacetate] ratios similar to those reported for livers of fed rats. Stimulation of 45Ca2+ efflux elicited by either 8-CPT-cAMP, a cAMP analog, or high glucagon concentrations (1 X 10(-8) M) was not affected whether livers were perfused with pyruvate (2.0 mM) or lactate (2.0 mM). Administration of isobutylmethylxanthine (50 microM) alone, or glucagon (1 X 10(-9) M) in the presence of isobutylmethylxanthine (50 microM) stimulated 45Ca2+ efflux from livers of 24-h-fasted animals perfused with pyruvate (2.0 mM) but not from livers perfused with lactate (2.0 mM). The ability of glucagon (1 X 10(-9) M) to elevate tissue cAMP levels was also regulated by the oxidation-reduction state of the livers. The data indicate that glucagon-stimulated 45Ca2+ efflux from perfused livers is mediated via cAMP and is dependent on the oxidation-reduction state of the livers.
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PMID:Glucagon-stimulated calcium efflux in the isolated perfused rat liver is dependent on cellular redox potential. 244 42

The effect of angiotensin II (AII) on adenylate cyclase was studied in the rat and rabbit heart sarcolemma. AII inhibited adenylate cyclase activity in the rat and rabbit sarcolemma in a concentration-dependent manner. Maximal inhibition of about 35-40% was observed in the rat, with an apparent Ki of about 3 nM; about 30% inhibition, with an apparent Ki of about 6 nM, was noted in rabbit sarcolemma. The inhibitory effect of AII was dependent on the presence of guanine nucleotides and was blocked by saralasin. In addition, AII also inhibited the stimulatory effects of isoproterenol and glucagon on adenylate cyclase. Ninhibin, a sperm factor which has been shown to modify the characteristics of inhibitory guanine nucleotide regulatory protein (Gi), attenuated the inhibitory effects of AII on basal and hormone-sensitive adenylate cyclase. Furthermore, pertussis toxin (PT) treatment of the sarcolemma in the presence of [32P]NAD resulted in ADP-ribosylation of a single 41-kD protein. PT also attenuated the AII-mediated inhibition of basal and hormone-sensitive adenylate cyclase and enhanced the magnitude of the stimulatory effects of isoproterenol and glucagon on adenylate cyclase activity. These data suggest that the rat myocardial sarcolemma contains AII receptors that are negatively coupled to adenylate cyclase through Gi protein.
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PMID:Angiotensin II receptors negatively coupled to adenylate cyclase in rat myocardial sarcolemma. Involvement of inhibitory guanine nucleotide regulatory protein. 249 5

The effects of glucagon and insulin on liver nuclear poly(ADP-ribose) polymerase activity and blood ketone body ratio after rat partial (68%) hepatectomy were examined. Liver weight regeneration rate was enhanced by glucagon and insulin after 5th posthepatectomy day. The maximal value of poly(ADP-ribose) polymerase activity without glucagon and insulin was revealed as 368 +/- 64 pmole/mg/min on 5 days after the hepatectomy. In contrast, the enzyme activity with glucagon and insulin reached to the peak value as 253 +/- 42 pmole/mg/min on 2 days after the hepatectomy. The amounts of DNA per nuclear protein showed similar changes with the changes of poly (ADP-ribose) polymerase activity after the hepatectomy. Blood ketone body ratio showed almost similar changes in both groups, except transitional decrease in the group without glucagon and insulin on 5th postoperative day. It is suggested that, to promote remnant liver regeneration, the combined therapy of glucagon and insulin may act directly to nucleic acid metabolism through the changes of poly(ADP-ribose) polymerase activity and preserve energy charge level by the suppression of NAD consumption by massive poly(ADP-ribose) formation.
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PMID:[Effects of glucagon and insulin on poly(ADP-ribose) polymerase activity and blood ketone body ratio after partial hepatectomy in rats]. 250 88

When hepatocytes isolated from adult rats were cultured in the presence of 10 mM nicotinamide, insulin- and epidermal growth factor-induced DNA synthesis and cell proliferation were found to be greatly stimulated, and the cells were able to be kept alive for more than one month. In the nicotinamide-treated hepatocytes, albumin and tryptophan 2,3-dioxygenase mRNAs were present at much higher levels than in the untreated control, and the inducibility of tryptophan oxygenase gene expression by dexamethasone and glucagon was also preserved. Without nicotinamide, primary cultured hepatocytes were viable for only 5-7 days and the hepatocyte-specific phenotypes were rapidly lost. The intracellular NAD level was maintained in the nicotinamide-treated hepatocytes at or above the level in intact liver but depleted in hepatocytes without nicotinamide. These results suggest that the maintenance of the intracellular NAD level is essential for the growth and functioning of hepatocytes and that nicotinamide can preserve the NAD level by blocking NAD degradation as well as by acting as a precursor for NAD synthesis.
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PMID:Nicotinamide prolongs survival of primary cultured hepatocytes without involving loss of hepatocyte-specific functions. 252 46

We have examined the influence of extracellular pH and calcium concentration on the action of glucagon on isolated rat hepatocytes, perfused liver or plasma membrane preparations. Incubation of rat hepatocytes with 10 nM glucagon at pH 7.4 caused an immediate increase in cAMP concentrations (8-fold), and this rise was almost 50% lower at acidic extracellular pH (6.9). This effect of pH could not be explained by an alteration of the hormone binding to its receptor for glucagon concentrations higher than 1 nM. The effect of acidosis on cAMP production was still present with non-hormonal effectors, such as 10 microM Gpp[NH]p, 30 microM forskolin or 10 mM NaF. This suggests a direct action of acidosis on the regulatory component Ns and/or on the catalytic subunit of adenylate cyclase. Acidic pH also depressed mitochondrial processes responsive to glucagon (NAD(P)H fluorescence, glutamine breakdown). Whatever the experimental model, calcium appeared to be required for maximal stimulation of cAMP production by glucagon. On perfused rat liver, glycogenolysis was depressed in the absence of extracellular calcium in the perfusate. In isolated hepatocytes, the stimulation of phosphorylase alpha activity by glucagon was modulated by extracellular calcium concentrations lower than 0.2 mM. This suggests that, although glucagon action is chiefly cAMP-mediated, its effect on calcium mobilization (affecting various cellular process, including cAMP production itself) should also be taken into account. This work also confirmed the importance of calcium in the stimulation of mitochondrial metabolism of glutamine by glucagon.
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PMID:Modulation of glucagon effects by changes in extracellular pH and calcium. 282 79

Isolated mouse liver mitochondria incubated with streptozotocin showed decreased rate and extent of Ca2+ uptake, and, dependent on the concentration of streptozotocin and the addition of alpha-ketoglutarate, glutamate, fluorocitrate or guanosine 5'-triphosphate, the retention of Ca2+ was either increased or decreased. Similar observations were made in liver mitochondria incubated with succinyl-CoA. In mitochondria isolated from the kidneys and islets of mice injected with streptozotocin, with and without additional injections of glucose and/or glucagon, the rate and extent of Ca2+ uptake were reduced and the release of accumulated Ca2+ was stimulated. Electron microscopy and X-ray microanalysis showed dislocation of Ca2+-containing precipitates from the mitochondria to the cytosol, and stereology disclosed increased mitochondrial volume in the B cells of streptozotocin-treated mice. State 3 and state 4 respiration with NAD-linked substrates was inhibited, but succinate oxidation was unaffected, in mitochondria isolated from the kidneys of mice treated with streptozotocin. In the kidneys of streptozotocin-injected mice, the concentration of succinyl-CoA was increased, that of citrate and guanosine 5'-triphosphate was decreased, that of glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-diphosphate was unaffected, and the metabolite concentration ratios suggested increased mitochondrial [NAD+]/[NADH] ratio and decreased cytoplasmic [NAD+]/[NADH] ratio. It is suggested as a new hypothesis that the cytotoxicity and the diabetogenicity of streptozotocin are dependent on inhibited citric acid cycle enzyme activity (primarily that of succinyl-CoA synthetase and citrate synthetase) with altered metabolite concentrations, leading to impairment of the mitochondrial uptake of Ca2+ and the activation of the pyruvate, isocitrate and alpha-ketoglutarate dehydrogenases.
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PMID:Mitochondrial changes and associated alterations induced in mice by streptozotocin administered in vivo and in vitro. 288 8

A significant stimulation of the 24-h (between day 4 and 5 in vitro) new DNA synthetic activity was elicited in primary neonatal rat hepatocytes kept in low-calcium (0.01 mmol/l) HiWoBa2000 synthetic medium by the addition of a single dose (10(-10) mol/l) of each of several tumour promoters [i.e. 12-O-tetradecanoylphorbol-13-acetate (TPA), phenobarbital, nafenopin, saccharin, teleocidin, benzoyl peroxide butylhydroxytoluene (BHT), dichlorodiphenyltrichloroethane (DDT), lindane, clofibrate and melittin]. Even hormones [e.g. epidermal growth factor (EGF), glucagon and insulin at 10(-10) mol/l] and EGF-like acting drugs (i.e. imidazole and indomethacin, at 10(-11) mol/l) similarly enhanced with respect to untreated controls the 24-h flow into S phase of the primary hepatocytes on condition, however, that the cells were incubated in a high- (i.e. 1.8 mmol/l) and not a low-calcium HiWoBa2000 medium. Xenobiotics, peptide mitogens and EGF-like acting drugs also enhanced the in vitro hepatocellular mitotic activity. The growth-stimulatory effects of the aforementioned eleven tumour promoters were entirely suppressed by the simultaneous addition to the growth medium of a fully effective dose (10(-4) - 10(-3) mol/l) of agents, such as 3-aminobenzamide (3-ABA), 3-methoxybenzamide (3-MBA) or nicotinamide (NA), that are known to inhibit the activity of ADP-ribosyl transferase (ADPRT). However, under the same conditions these inhibitors hampered neither the basal DNA synthetic and mitotic activities of spontaneously cycling hepatocytes nor the stimulation of the hepatocellular growth processes evoked by peptide mitogens and EGF-like acting drugs. Quantitative autoradiographic investigations showed that the incorporation of the ADP-ribose precursor and ADPRT substrate [3H]NAD into nuclear macromolecules of gently digitonin-permeabilized hepatocytes was negligible in the untreated cultures, whereas it was strikingly and nearly steadily increased by a 2-, 8- and 24-h exposure to a fully mitogenic dose (10(-10) mol/l) of TPA, thereby revealing that an early, significant and roughly steady activation of the nuclear ADPRT had taken place in the phorbol ester-treated liver parenchymal cells. The simultaneous addition of 3-ABA (10(-4) mol/l) not only fully checked the mitogenic effects of TPA, but even suppressed about two-thirds of the TPA-elicited nuclear incorporation of [3H]NAD by the permeabilized hepatocytes, thus showing that a significant curtailment of the TPA-activated ADPRT did occur is association with the abatement of the mitogenic effects of TPA by this inhibitor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibitors of ADP-ribosyl transferase suppress the mitogenic actions exerted by tumour promoters, but not those evoked by peptide mitogens, in primary neonatal rat hepatocytes. 297 75

The present study was undertaken to investigate the acute and long-term effects of streptozotocin (SZ) on pancreatic islet function and survival in vitro. Isolated mouse pancreatic islets, that had been cultured overnight, were exposed to SZ (0.55-4.4 mM) or critic acid buffer in the case of the control group. The islets were examined either immediately after SZ exposure or after one week in culture. There was a marked loss of islets treated with 2.2 and 4.4 mM SZ during the culture; however, the DNA content of the remaining islets was unaffected. The islet insulin content was reduced 7 days after treatment with 2.2 and 4.4 mM SZ. At 4.4 mM the glucagon and somatostatin content of the islet was also decreased but not to the same degree as the insulin content. SZ-induced inhibition of glucose-stimulated insulin release and (pro)insulin biosynthesis was more pronounced on day 7 as compared to day 0. A similar pattern of inhibitory action of SZ was observed on islet glucose oxidation rates. Islet ATP contents were depressed on day 7 in islets exposed 4.4 mM SZ, but were otherwise similar to the control group. Islet NAD + NADH contents were decreased by 50% after exposure to 2.2 mM SZ, compared to the control islets on day 0. This decrease in NAD + NADH contents was to a large extent restored during the one-week culture. The present study shows that islets failed to completely repair the acute damage caused by SZ, and that the impairment of the islet glucose-stimulated insulin release induced by SZ seemed to progress in culture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional characteristics of cultured mouse pancreatic islets following exposure to different streptozotocin concentrations. 297 3

Islet-activating protein (IAP, a Bordetella pertussis toxin) was employed to test the hypothesis that the inhibitory GTP-binding regulatory protein of adenylate cyclase (Ni) mediates GTP effects on the binding of Ca2+-mobilizing hormones to liver plasma membranes and is involved in calcium mobilization stimulated by these agonists. IAP added to normal liver plasma membranes catalyzed the incorporation of radioactivity from [32P]NAD into a 41,000-Da peptide (presumably the alpha-subunit of Ni). However, no such incorporation was observed in liver membranes prepared from rats 24 hr after intraperitoneal injection of IAP. Angiotensin II attenuated glucagon-stimulated increases in cAMP in hepatocytes prepared from control but not IAP-treated rats. In contrast, following IAP treatment, no changes were observed in the ability of glucagon, vasopressin, angiotensin II, or epinephrine to activate phosphorylase; nor did this treatment alter [3H]vasopressin binding or epinephrine displacement of [3H]prazosin binding. However, IAP treatment decreased [3H]angiotensin II binding affinity when studies were performed in the absence but not the presence of 5'-guanylylimidodiphosphate (GppNHp). This shift was small and represented only 5-8% of the shift in apparent Kd elicited by GppNHp in untreated membranes. In vitro studies with IAP confirmed the results of the radioligand binding studies using in vivo IAP treatment. The effects of NaCl on [3H]angiotensin II binding were also tested but were not typical of other receptors which couple to Ni. The data suggest that, although a small population of hepatic angiotensin II receptors couple to Ni and attenuate glucagon-stimulated increases in cAMP, vasopressin, alpha 1-adrenergic, and the majority of angiotensin II receptors do not interact significantly with Ni. Thus, although there is evidence that agonist-induced Ca2+ mobilization requires a GTP-binding regulatory protein, this protein does not appear to be Ni in rat liver.
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PMID:Effect of islet-activating pertussis toxin on the binding characteristics of Ca2+-mobilizing hormones and on agonist activation of phosphorylase in hepatocytes. 300 28

Acute administration of glucagon to the rat in vivo inhibits hepatic polypeptide chain elongation by about 30%. This effect was not observed in adrenalectomized rats, despite the significant increases in the hepatic content of cyclic AMP. Fatty acid administration mimics the glucagon action on protein synthesis; however, in adrenalectomized animals they were ineffective. Whether glucagon or fatty acids were administered, there was a significant increase in the state of reduction of the NAD system in normal as well as in adrenalectomized rats. This observation rules out the change in the cellular state of reduction as the mediator of their action on protein synthesis. A correlation was observed between the ability of glucagon or fatty acids to inhibit protein synthesis and to stimulate gluconeogenesis. An increased biosynthetic activity as reflected by an increased gluconeogenic flux is accompanied by a decreased phosphorylation state of adenine nucleotides that might be responsible for the inhibitory effect on protein synthesis. In adrenalectomized animals in which neither glucagon nor fatty acids stimulate gluconeogenesis, no effects on phosphorylation state or on the rate of protein synthesis were detected.
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PMID:Interrelation between gluconeogenesis and hepatic protein synthesis. 301 33

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