Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The efflux of GSH has been shown previously to be a saturable process in both isolated rat hepatocytes and perfused liver, suggesting a carrier-mediated transport mechanism. The possibility in hormonal regulation of this process has been raised by recent reports. Our present work examined the role of hormones known to affect intracellular signal transduction mechanisms on GSH efflux in cultured rat hepatocytes and perfused rat livers. We found that cAMP-dependent factors, such as cholera toxin (CT), dibutyryl cAMP, forskolin, and glucagon all stimulated GSH efflux in cultured rat hepatocytes. The efflux kinetics were compared in cultured cells incubated with or without CT; the stimulation of GSH efflux was related to a near doubling of the Vmax while exhibiting no significant alteration of the Km. The increase in intracellular cAMP level associated with the threshold for this stimulatory effect was 25% above control. The stimulatory effect of CT could not be blocked by cyclohexamide pretreatment or reversed by colchicine treatment. The stimulatory effect of glucagon was abolished in the presence of ouabain but not in the presence of barium. On the other hand, hormones which act through Ca2+ and protein kinase C, such as phenylephrine and vasopressin, had no effect on GSH efflux in the cultured cells. In the perfused liver model, glucagon (10 nM) and dibutyryl cAMP (8 microM) stimulated sinusoidal GSH efflux to 130 and 144% of control values, respectively, and increased bile flow while not affecting biliary GSH efflux. Finally, the physiological significance of glucagon-mediated stimulation of sinusoidal GSH efflux was assessed by both plasma GSH and glucose levels in response to in vivo glucagon infusion. The threshold dose of glucagon for significant increase in plasma GSH (5.21 pmol/min) was lower than for glucose (15.61 pmol/min). At the highest glucagon infusion rate (261 pmol/min), plasma GSH level doubled while glucose level increased 80%. In conclusion, increased cAMP stimulates GSH efflux in cultured rat hepatocytes and perfused livers. The stimulatory effect of cAMP is exerted at the sinusoidal pole and appears to be mediated by hyperpolarization of hepatocytes by stimulation of Na(+)-K(+)-ATPase. In vivo studies confirmed the importance of cAMP-mediated stimulation of sinusoidal GSH efflux as it resulted in significant elevation of the plasma GSH level.
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PMID:Hormonal regulation of glutathione efflux. 216 79

The cellular mechanism by which the angiotensin II (AII) agonist, Sar1-AII, inhibits production and release of angiotensinogen in human hepatoma HepG2 cells was examined. Pretreatment of HepG2 cells with pertussis toxin attenuated the ability of Sar1-AII to block angiotensinogen production. This effect could be correlated with the in situ ADP-ribosylation of a protein(s) of apparent molecular weight 39,000-41,000 on SDS-PAGE, and attenuation of the ability of Sar1-AII to inhibit cAMP accumulation. The role of cAMP in angiotensinogen production was examined. A transient increase in cAMP accumulation above basal could be evoked by forskolin (8-fold) or by glucagon (5-fold) using insulin-deficient media. Although neither forskolin nor glucagon had a significant effect on angiotensinogen production agents producing a sustained increase in intracellular cAMP (8-bromo-cAMP, dibutyryl-cAMP, cholera toxin) were able to increase angiotensinogen production. Although these data indicate that intracellular cAMP is a regulatory factor in angiotensinogen production other evidence suggests that modulation of intracellular cAMP is not entirely responsible for the effects of Sar1-AII.
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PMID:Involvement of a pertussis toxin-sensitive G protein in the regulation of angiotensinogen production by an angiotensin II analog in HepG2 cells. 217 1

Addition of vasopressin (100 nM) to rat hepatocytes prelabelled with [3H]inositol stimulated the production of inositol phosphates in the presence of 20 mM Li+. Preincubation of hepatocytes with insulin (50 nM) or glucagon (10 nM) had no significant effect alone but enhanced the effects of vasopressin after a lag period of at least 1 min. The effects of insulin and glucagon appeared additive in this respect. Insulin also enhanced the norepinephrine-mediated stimulation of inositol phosphate accumulation. The enhancement by insulin of the effects of vasopressin required at least 0.5-5 nM insulin and did not involve changes in [3H]inositol lipid labelling or IP3 phosphatase activity. The effect of insulin appeared insensitive to prior treatment of hepatocytes with pertussis toxin (200 ng/ml for 18-24 h) or cholera toxin (100 ng/ml for 3-4 h). The glucagon enhancement of the effects of vasopressin was not affected by pertussis toxin but was mimicked by cholera toxin. The response of hepatocytes to vasopressin in the absence of Li+ was smaller and more transient. Under these conditions a 5 min prior incubation with insulin inhibited the stimulation by vasopressin of inositol phosphate accumulation. A similar inhibitory effect of prior insulin exposure on the transient activation by vasopressin of exogenous phosphatidylinositol 4,5-bisphosphate breakdown by hepatocyte homogenates was also seen. These data indicate that insulin, although having no effect on basal inositol phosphate accumulation, can either enhance or antagonise the effects of vasopressin in primary rat liver hepatocyte cultures depending on the experimental conditions.
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PMID:Effects of insulin on inositol phosphate production in cultured rat hepatocytes. 218 Apr 88

Exposure of cultured hepatocytes to glucagon leads to a partial refractoriness of the adenylate cyclase both to glucagon (homologous desensitization) and to isoproterenol (heterologous desensitization). In contrast, isoproterenol produces a very strong homologous desensitization but almost no heterologous desensitization. The present study compared the pattern of the homologous and heterologous components of glucagon-induced desensitization in these cells, particularly during the first 4 hours, and examined the role of cyclic 3',5'-adenosine monophosphate (cAMP) in the mechanism of refractoriness development. The decrease in glucagon-sensitive and isoproterenol-sensitive adenylate cyclase activities were closely parallel with respect to the extent, the time course and the dose required. 8-Bromoadenosine 3',5'-monophosphate (8-Bromo-cAMP) also reduced the hormone-responsive adenylate cyclase activity, but this effect developed more slowly than the desensitization after glucagon treatment. No consistent relationship was found between cAMP levels and induction of hormone refractoriness when the cells were exposed to glucagon, isoproterenol, cholera toxin or forskolin. Furthermore, addition of 0.5 mM 3-isobutyl-1-methylxanthine) (IBMX) which strongly amplified the cAMP response, did not potentiate the glucagon-induced desensitization of either glucagon-sensitive or isoproterenol-sensitive adenylate cyclase activity. Taken together, the results suggest that homologous and heterologous desensitization of the adenylate cyclase developing after glucagon exposure occur by similar (agonist-non-specific) mechanisms which do not involve cAMP.
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PMID:Glucagon-induced refractoriness of hepatocyte adenylate cyclase: comparison of homologous and heterologous components and evidence against a role of cAMP. 247 64

Adenylate cyclase in liver plasma membranes from streptozotocin-diabetic (STZ) or BB/Wor spontaneously diabetic rats showed increased responsiveness to GTP, glucagon, fluoroaluminate, and cholera toxin. Basal or forskolin-stimulated activity was unchanged in STZ rats, but increased in BB/Wor rats. No change in the alpha-subunit of Gi (alpha i) was observed in STZ or BB/Wor rats using pertussis toxin-stimulated [32P]ADP-ribosylation. Immunodetection using antibodies against the COOH-terminal decapeptides of alpha T and alpha i-3 showed no change in alpha i in STZ rats and a slight decrease in BB/Wor rats. Angiotensin II inhibition of hepatic adenylate cyclase was not altered in either diabetic rat. In both models of diabetes, Gs alpha-subunits were increased as measured by cholera toxin-stimulated [32P]-ADP-ribosylation of 43-47.5-kD peptides, reconstitution with membranes from S49 cyc- cells or immunoreactivity using antibodies against the COOH-terminal decapeptide of alpha s. These data indicate that STZ-diabetes increases hepatic Gs but does not change Gi or adenylate cyclase catalytic activity. In contrast, BB/Wor rats show increased hepatic Gs and adenylate cyclase. These changes could explain the increase in hepatic cAMP and related dysfunctions observed in diabetes.
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PMID:Guanine nucleotide binding regulatory proteins and adenylate cyclase in livers of streptozotocin- and BB/Wor-diabetic rats. Immunodetection of Gs and Gi with antisera prepared against synthetic peptides. 249 95

Expression of the gene encoding preproglucagon gives rise to different glucagon-related peptides in the pancreas and intestine. Glucagon gene expression is regulated by a protein kinase C-dependent pathway in rat islet cell lines, whereas activation of the adenylate cyclase pathway in islet cell lines is without effect. To elucidate the factors important for the control of proglucagon biosynthesis in the intestine, we have studied proglucagon gene expression and proglucagon biosynthesis in rat intestine. Analysis of intestinal cDNA clones encoding preproglucagon indicated that pancreatic and intestinal glucagon mRNA transcripts were identical. The regulation of proglucagon gene expression in rat intestine differed markedly from that previously observed in islet cell lines. Phorbol esters increased the secretion of glucagon-like immunoreactive peptides (GLI) but had no effect on proglucagon mRNA levels in rat intestinal cells. Bombesin also increased the secretion of GLI without affecting proglucagon mRNA levels or biosynthesis. In contrast, dibutyryl cyclic AMP, forskolin, and cholera toxin increased both proglucagon mRNA levels and GLI biosynthesis and secretion, suggesting that proglucagon gene expression in the intestine is regulated by a cyclic AMP-dependent pathway. These observations suggest that tissue-specific differences in both the regulation of proglucagon gene expression and the posttranslational processing of proglucagon contribute to the diversity of glucagon gene expression.
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PMID:Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine. 254 59

Hepatocyte membranes from both lean and obese Zucker rats exhibited adenylate cyclase activity that could be stimulated by glucagon, forskolin, NaF and elevated concentrations of p[NH]ppG. In membranes from lean animals, functional Gi was detected by the ability of low concentrations of p[NH]ppG to inhibit forskolin-activated adenylate cyclase. This activity was abolished by treatment of hepatocytes with either pertussis toxin or the phorbol ester TPA, prior to making membranes for assay of adenylate cyclase activity. In hepatocyte membranes from obese animals no functional Gi activity was detected. Quantitative immunoblotting, using an antibody able to detect the alpha subunit of Gi, showed that hepatocyte plasma membranes from both lean and obese Zucker rats had similar amounts of Gi-alpha subunit. This was 6.2 pmol/mg plasma membrane for lean and 6.5 pmol/mg plasma membrane for obese animals. Using thiol pre-activated pertussis toxin and [32P]-NAD+, similar degrees of labelling of the 40 kDa alpha subunit of Gi were found using plasma membranes of both lean and obese Zucker rats. We suggest that liver plasma membranes from obese Zucker rats express an inactive Gi alpha subunit. Thus lesions in liver Gi functioning are seen in insulin-resistant obese rats and in alloxan- and streptozotocin-induced diabetic rats which also show resistance as regards the acute actions of insulin. Liver plasma membranes of obese animals also showed an impairment in the coupling of glucagon receptors to Gs-controlled adenylate cyclase, with the Kd values for activation by glucagon being 17.3 and 126 nM for lean and obese animals respectively. Membranes from obese animals also showed a reduced ability for high concentration of p[NH]ppG to activate adenylate cyclase. The use of [32P]-NAD+ and thiol-preactivated cholera toxin to label the 43 kDa and 52 kDa forms of the alpha-subunit of Gs showed that a reduced labelling occurred using liver plasma membranes from obese animals. It is suggested that abnormalities in the levels of expression of primarily the 52 kDa form of alpha-Gs may give rise to the abnormal coupling between glucagon receptors and adenylate cyclase in liver membranes from obese (fa/fa) Zucker rats.
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PMID:Multiple defects occur in the guanine nucleotide regulatory protein system in liver plasma membranes of obese (fa/fa) but not lean (Fa/Fa) Zucker rats: loss of functional Gi and abnormal Gs function. 256 40

The effect of in ovo administration of ovine growth hormone (oGH) on growth and adipose tissue development of chickens was investigated. Unlike mammalian species, exogenous growth hormone has not been previously shown to increase growth of aves. In trial 1, fertilized eggs were injected with vehicle (.03 M NaHCO3 in .15 M NaCl, pH 8.3), 0.25, 2.5, 25 or 250 micrograms oGH on day 11 of embryogenesis. In trial 2, fertile eggs were injected with vehicle or 250 micrograms oGH. In contrast to previous studies in which GH was administered to growing birds, oGH injected in ovo in the present study increased body weights, skeletal growth and feed efficiencies of male broilers. Growth rate was not altered in females. Adipose cellularity data from both trials indicated that in ovo oGH also altered adipose tissue development of broilers. Seven-week-old male and female broilers treated with oGH during embryogenesis exhibited larger adipocytes with correspondingly less cell per gram of tissue. Additionally, adipocytes from oGH-treated broilers exhibited decreased sensitivity to glucagon, cholera toxin or theophylline-induced lipolysis responsiveness to dcAMP in ovo. Cholera toxin plus theophylline improved the lipolytic response of oGH-treated birds; thus, in broilers injected with oGH cAMP-mediated lipase activation may be reduced by a mechanism of increased phosphodiesterase activity. The results of this study indicate that growth and tissue development of chickens have been altered by mammalian GH in ovo.
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PMID:In ovo growth hormone alters growth and adipose tissue development of chickens. 259 45

The effect of various factors and substrates on the growth of a human hepatoblastoma cell line, HuH-6, which was inoculated at low density in a serum-free medium was examined. Several supplements were required to enhance cell growth of HuH-6. These included cholera toxin (CT), glucagon (Glu) and selenium (Se). Type IV collagen (C-IV) provided the most conductive environment tested for cell growth. These results suggest that CT, Glu, Se, and C-IV are important stimulators for the continuous growth of HuH-6 in a serum-free medium at low density.
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PMID:Effect of various factors and substrates on the growth of a human hepatoblastoma cell line, HuH-6 in a serum-free medium. 262 43

The regulatory properties of adenylate cyclase in small intestinal mucosa were investigated. Glucagon, epinephrine and isoproterenol failed to activate the cAMP synthesis; prostaglandin E1 caused a 2.8-fold, while cholera toxin-a 4.5-fold stimulation. The latter was not able to increase the rate of glucose synthesis from alanine in vitro, but increased markedly the in vivo incorporation of 14C-labeled alanine into the mucus glucosamine. Unlabeled glucosamine excretion was also enhanced 3-fold. This provides evidence for the involvement of glycolysis and gluconeogenesis enzyme systems in the mucosal glycoprotein synthesis. It was assumed that both metabolic pathways may play a common physiological role, namely, to convert carbohydrates and gluconeogenic precursors into the substrate for glucosamine synthesis which is thought to be a rate-limiting step in small intestinal mucus secretion.
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PMID:[Relation between glycoprotein synthesis and carbohydrate metabolism in the small intestine mucosa. Effect of cholera enterotoxin]. 283 Sep 17


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