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)

Evidence suggests that ethanol desensitizes hepatocytes to the trophic effects of hormones. Cyclic AMP-dependent signals are important regulators of intermediary metabolism, cellular proliferation and differentiation, and modulate liver growth during hepatic regeneration. The events leading to cyclic AMP accumulation after partial hepatectomy were characterized in rats consistently fed ethanol-containing diets and compared with results in rats fed isocaloric amounts of nonethanol diet to determine whether altered cyclic AMP-dependent signal transduction contributes to ethanol-associated aberrations in hepatic growth regulation. Ethanol treatment significantly inhibited hepatic accumulation of cyclic AMP after partial hepatectomy. This was most likely the result of decreased synthesis of cyclic AMP because activation of adenylyl cyclase by agents acting through receptors (e.g., glucagon or isoproterenol), GTP-binding proteins (GTP-gamma-S) and directly on adenylyl cyclase (e.g., forskolin) was significantly inhibited in ethanol-fed rats. Both homologous and heterologous desensitization contributed to this effect. beta 1-Adrenergic receptors were relatively down-regulated 6 hr after partial hepatectomy in ethanol-fed rats, whereas glucagon receptor kinetics were similar in the two groups. Liver membrane expression of GTP-binding proteins differed markedly after partial hepatectomy in ethanol-fed and pair-fed rats. Ethanol significantly inhibited post-partial hepatectomy induction of the stimulatory G protein, Gs alpha but led to overexpression of the inhibitory, G(i)2 alpha, subunit. Steady-state messenger RNA levels of these G proteins were similar in ethanol-fed and pair-fed rats, suggesting that ethanol inhibits G protein expression posttranscriptionally.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chronic ethanol consumption disturbs G-protein expression and inhibits cyclic AMP-dependent signaling in regenerating rat liver. 133 Aug 68

Treatment of chick hepatocytes with glucagon results in homologous and heterologous desensitization of the receptor-stimulated adenylyl cyclase. The loci of postreceptor heterologous desensitization was studied. The addition of excess purified GS to glucagon-desensitized hepatocyte membranes did not fully restore fluoride stimulation of adenylyl cyclase, even though the absolute activity was increased at least 2-fold. Treatment of chick hepatocytes with 8-bromo-cAMP resulted in a similar reduction of fluoride stimulation that could not be restored by the addition of purified GS. When membranes from control and glucagon-treated hepatocytes were treated with purified catalytic subunit of protein kinase-A (PKA), fluoride stimulation was lowered in control, but not glucagon-treated, membranes. Treatment of membranes from S49 kin- lymphoma cells with PKA also resulted in decreased fluoride- and forskolin-stimulated adenylyl cyclase activity, but activity stimulated by Mn2+ was not altered. Since previous studies from our laboratory had shown that GS and G(i) are not substrates for protein kinase-A, it appears that the catalyst of adenylyl cyclase is the likely locus of modulation. To determine if both chick hepatocytes and S49 cells contain similar types of adenylyl cyclase that could account for the similar PKA regulatory properties, we used polymerase chain reaction-based techniques to identify GS-stimulated adenylyl cyclases present in these systems. The chick liver contains both type 5 and type 6 adenylyl cyclases, while S49 cells contain the type 6 enzyme. Type 5 and 6 adenylyl cyclases are members of one widely expressed subfamily of mammalian GS-responsive adenylyl cyclases and share a predicted PKA phosphorylation site in the central cytoplasmic loop. This site is not found in other known adenylyl cyclases (types 1-4), although the olfactory-specific type 3 enzyme has a predicted site nearby. These data indicate that one component of hormone-induced desensitization of the adenylyl cyclase system can be at the level of the catalyst, where PKA-mediated phosphorylation could result in lowered responsiveness. The types 5 and 6 adenylyl cyclases are likely candidates for such regulation.
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PMID:Lowered responsiveness of the catalyst of adenylyl cyclase to stimulation by GS in heterologous desensitization: a role for adenosine 3',5'-monophosphate-dependent phosphorylation. 133 48

The stimulatory effect of Mn2+ (1.5-fold), forskolin (1.6-fold) and low (1 microM) concentrations of GTP (1.9-fold) on the adenylyl cyclase of adipocyte membranes from obese, diabetic CBA/Ca mice was markedly enhanced compared to that seen using membranes prepared from their lean littermates. In contrast, receptor-mediated stimulation, achieved with either isoprenaline or secretin was reduced and that by glucagon abolished in membranes from diabetic animals. The levels of expression of alpha-subunits of Gi-1, Gi-2 and Gi-3 were reduced to some 49, 76 and 54%, respectively, in membranes from diabetic animals compared with those from normal animals. Levels of G-protein beta-subunits and Gs alpha-subunits were similar. Receptor-mediated inhibition of adenylate activity elicited by either nicotinic acid or prostaglandin E1 (PGE1) was of a similar magnitude in membranes from normal and diabetic animals but the inhibitory action of N6-(L-2-phenylisopropyl)adenosine (PIA) was greater in membranes from diabetic animals by about 30%. Gi function was similarly evident in membranes from both lean and diabetic animals, as assessed using low concentrations of guanylyl 5'-imidodiphosphate to inhibit forskolin-stimulated adenylyl cyclase activity. However, assessing Gi function using GTP showed marked dissimilarities in that the elevated GTP concentrations expected to occur physiologically were incapable of reversing the stimulation achieved at low concentrations of GTP in membranes from diabetic but not normal animals. The adipocytes of CBA/Ca mice, as do other animal models of insulin resistance, show lesions in adenylyl cyclase regulation, Gi function and G-protein expression.
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PMID:Alterations in G-protein expression, Gi function and stimulatory receptor-mediated regulation of adipocyte adenylyl cyclase in a model of insulin-resistant diabetes with obesity. 141 80

Incubation of Candida albicans yeast cells with human luteinizing hormone (hLH), human chorionic gonadotrophin (hCG) or glucagon produced a significant rise in cAMP total levels. The effect of these hormones in permeabilized cells of the fungus produced a 2-3 fold increase in the Mg2+, GTP-dependent adenylyl cyclase activity as well as full activation of the cAMP-dependent protein kinase (PKA) activity. These results indicate that the interaction of the mammalian hormones with the fungus triggered the cAMP activation cascade in a similar way to that found in higher eukaryotic organisms.
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PMID:Activation of the cAMP cascade by steroidogenic hormones and glucagon in the pathogenic fungus Candida albicans. 185 67

Liver plasma membranes prepared from genetically diabetic (db/db) mice expressed levels of Gi alpha-2, Gi alpha-3 and G-protein beta-subunits that were reduced by some 75, 63 and 73% compared with levels seen in membranes from lean animals. In contrast, there were no significant differences in the expression of the 42 and 45 kDa forms of Gs alpha-subunits. Pertussis toxin-catalysed ADP-ribosylation of membranes from lean animals identified a single 41 kDa band whose labelling was reduced by some 86% in membranes from diabetic animals. Cholera toxin-catalysed ADP-ribosylation identified two forms of Gs alpha-subunits whose labelling was about 4-fold greater in membranes from diabetic animals compared with those from lean animals. Maximal stimulations of adenylyl cyclase activity by forskolin (100 microM), GTP (100 microM), p[NH]ppG (100 microM), NaF (10 mM) and glucagon (10 microM) were similar in membranes from lean and diabetic animals, whereas stimulation by isoprenaline (100 microM) was lower by about 22%. Lower concentrations (EC50-60 nM) of p[NH]ppG were needed to activate adenylyl cyclase in membranes from diabetic animals compared to those from lean animals (EC50-158 nM). As well as causing activation, p[NH]ppG was capable of eliciting a pertussis toxin-sensitive inhibitory effect upon forskolin-stimulated adenylyl cyclase activity in membranes from both lean and diabetic animals. However, maximal inhibition of adenylyl cyclase activity in membranes from diabetic animals was reduced to around 60% of that found using membranes from lean animals. Pertussis toxin-treatment in vivo enhanced maximal stimulation of adenylyl cyclase by glucagon, isoprenaline and p[NH]ppG through a process suggested to be mediated by the abolition of functional Gi activity. The lower levels of expression of G-protein beta-subunits, in membranes from diabetic compared with lean animals, is suggested to perturb the equilibria between holomeric and dissociated G-protein subunits. We suggest that this may explain both the enhanced sensitivity of adenylyl cyclase to stimulation by p[NH]ppG in membranes from diabetic animals and the altered ability of pertussis and cholera toxins to catalyse the ADP-ribosylation of G-proteins in membranes from these two animals.
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PMID:Determination of G-protein levels, ADP-ribosylation by cholera and pertussis toxins and the regulation of adenylyl cyclase activity in liver plasma membranes from lean and genetically diabetic (db/db) mice. 193 44

We have recently shown that nanomolar concentrations of glucagon-(19-29), which can derive from native glucagon by proteolytic cleavage of the dibasic doublet Arg17-Arg18, inhibit the Ca2+ pump in liver plasma membrane vesicles independently of adenylyl cyclase activation (Mallat, A., Pavoine, C., Dufour, M., Lotersztajn, S., Bataille, D., and Pecker, F. (1987) Nature 325, 620-622). We report here that the regulation of the Ca2+ pump by glucagon-(19-29) is dependent on guanine nucleotides. In the presence of 10 microM guanosine 5'-3-O-(thio) triphosphate (GTP gamma S) or 75 microM GTP, glucagon-(19-29) caused a biphasic regulation of the Ca2+ pump. ATP-dependent Ca2+ transport was inhibited in the presence of 10 pM to 1 nM glucagon-(19-29), while higher concentrations of the peptide (1-100 nM) reversed the inhibition caused by lower ones. GTP gamma S alone, at high concentrations (100 microM), reproduced the inhibitory effect of glucagon-(19-29) and induced a 40% inhibition of the basal activity of the Ca2+ pump which was reversed by low concentrations of glucagon-(19-29) (10 pM to 1 nM). Treatment of rats with cholera toxin resulted in a 70% increase in the basal activity of the Ca2+ pump, a loss of sensitivity to GTP gamma S and to the biphasic regulation by glucagon-(19-29). Treatment with pertussis toxin did not affect the response of the Ca2+ pump to GTP gamma S and glucagon-(19-29). We conclude that glucagon-(19-29) can exert a biphasic effect on the Ca2+ pump which is mediated by G protein(s) sensitive to cholera toxin.
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PMID:Glucagon-(19-29) exerts a biphasic action on the liver plasma membrane Ca2+ pump which is mediated by G proteins. 214 Oct 22

Glucagon exerts positive inotropic and chronotropic effects in the heart. Like its glycogenolytic effect in liver cells, the cardiac effects of glucagon are often correlated with adenylyl cyclase stimulation. Therefore, cyclic AMP-dependent phosphorylation of L-type Ca2+ channels might be involved in the inotropic effect of glucagon. There have been no reports, however, of the effects of glucagon on the cardiac Ca2+ current (ICa). Also, the physiological effects of glucagon could involve mechanisms other than stimulation of adenylyl cyclase. Here we show that glucagon enhances ICa in frog and rat ventricular myocytes. The effect of glucagon in rats resulted from a stimulation of adenylyl cyclase. In frogs, however, the effect of glucagon on ICa was smaller and occurred at a concentration tenfold lower than in rats, and adenylyl cyclase was not modified. In addition, cAMP potentiated the effect of glucagon on ICa in frog ventricle, which correlated with the observed inhibition by glucagon of low-Km cAMP phosphodiesterase activity. Therefore, this is an example of a hormone that affects cardiac function in a similar way to a variety of synthetic cardiotonic compounds, such as milrinone and Ro-20-1724. Inhibition of phosphodiesterase activity by glucagon may be essential in animals in which glucagon increases cardiac contractility but does not effectively stimulate adenylyl cyclase.
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PMID:Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. 215 95

GTP, GTP-gamma-S and Gpp(NH)p produced a significant activation of Mg2(+)-dependent adenylyl cyclase in permeabilized cells of Candida albicans. This activation was inhibited by GDP-beta-S. Maximal stimulation (4-6 fold) was obtained when Mg2+ and GTP-gamma-S were added during permeabilization. The guanine nucleotide-stimulated activity could be further activated by glucagon in a dose dependent manner being the maximal stimulation (4-5 fold) attained at 10(-6) M glucagon. Addition of the hormone to yeast cells incubated under conditions conducive to produce germ tubes blocked hyphal development and promoted multibudded cell morphology.
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PMID:A guanine nucleotide-sensitive, glucagon-stimulated adenylyl cyclase in Candida albicans: effect of glucagon on cell morphology. 218 26

Glucagon-stimulated adenylyl cyclase activity has been shown to change in liver membranes manipulated to alter either their fatty acid composition or fluidity. We examined whether membrane alterations induced by dietary manipulation affected receptor function. Glucagon- and beta-adrenergic-stimulated receptor-adenylyl cyclase systems were examined in liver membranes of rats fed diets containing 10% corn oil, 10% coconut oil (essential FFA deficient), or 8.5% coconut oil with 1.5% corn oil (essential FFA repleat). Basal and maximal nonreceptor-mediated adenylyl cyclase activity (stimulated by NaF, guanylylimidodiphosphate, and forskolin) was the same in membranes of each of the dietary groups, suggesting that Gs-protein and the catalytic unit activity per se were unaltered by the manipulations. Glucagon-stimulated adenylyl cyclase activity increased with increasing unsaturation of dietary fatty acids; activity in coconut oil-fed rats was 527 +/- 30 (mean +/- SEM) pmol/mg.10 min, that in coconut/corn oil-fed rats was 752 +/- 74 pmol/mg.10 min, and that in corn oil-fed rats was 981 +/- 94 pmol cAMP/mg.10 min. [125I]Monoiodoglucagon binding did not increase in parallel to the adenylyl cyclase alterations; coconut oil-fed animals (614 fmol/mg) differed from the other groups (450 and 430 fmol/mg). Isoproterenol (beta-adrenergic)-stimulated adenylyl cyclase activity was also highest in the corn oil-fed animals, but was similar in the other dietary groups, with no difference in other characteristics of [125I]iodopindolol binding between the groups. The results demonstrate that alterations in the glucagon-stimulated adenylyl cyclase response are different from those in the beta-adrenergic adenylyl cyclase response. Further, they suggest that although direct activations of the catalytic unit or its interaction with the guanine nucleotide-sensitive protein are apparently not affected, hormone receptor-mediated adenylyl cyclase activity may be altered by these dietary manipulations.
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PMID:Altered glucagon- and catecholamine hormone-sensitive adenylyl cyclase responsiveness in rat liver membranes induced by manipulation of dietary fatty acid intake. 222 11

Indirect evidence has indicated that the carbohydrate moieties of the glycoprotein hormones are involved in the activation of the receptor-adenylyl cyclase system of reproductive tissues. In the present study, we have isolated the glycopeptides (GP) from human chorionic gonadotropin (hCG), the alpha-subunit of hCG, fetuin, and bovine gamma-globulin (b gamma G). These along with a number of synthetic oligosaccharides were tested for their ability to inhibit adenylyl cyclase (AC). There was less than 0.001% cross-reactivity of the GP from hCG, hCG alpha, fetuin, and b gamma G when tested in a double-antibody hCG radioimmunoassay or rat corpora lutea radioreceptor assay. The GP of fetuin, b gamma G, and the synthetic oligosaccharides did not inhibit AC activity of 2000 g corpora lutea membranes when coincubated with 100 ng of hCG/mL (ED50). However, when the GP of hCG and hCG alpha were included with intact hCG, there was a dose-related inhibition. Inhibition of cyclase activity was enhanced when the hCG GP were desialylated. This occurred without a change in the lag time of hCG activation which was calculated to be 1-1.5 min. Changing the concentration of ATP and Mg2+ did not affect the inhibitory effects of the hCG alpha GP on hCG-stimulated AC activity. Inhibition by hCG GP followed uncompetitive kinetics. The inhibition by the GP of hCG seems to be restricted to the LH/hCG-stimulatable AC system because the same dosage of hCG GP which inhibited the rat luteal AC system did not have any effect on the rat hepatocyte AC system when coincubated with glucagon or on NaF-stimulated activity in luteal membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of adenylyl cyclase activity in rat corpora luteal tissue by glycopeptides of human chorionic gonadotropin and the alpha-subunit of human chorionic gonadotropin. 241 22

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