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)

Glucagon increases the rate of glycogenolysis in in vitro cultures of hepatic tissue from the axolotl Ambystoma mexicanum. The hormone causes an increase in the concentration of cyclic AMP in the tissue which is followed by activation of glycogen phosphorylase and subsequent breakdown of glycogen and release of glucose from the tissue. Insulin counteracts the glycogenolytic effect of glucagon by inhibiting the increase in tissue cyclic AMP concentration brought about by glucagon. This inhibitory effect of insulin is not seen in the presence of the phosphodiesterase inhibitor IBMX and so it appears that the initial action of insulin is a stimulation of cyclic AMP phosphodiesterase activity which lowers the tissue concentration of cyclic AMP and so counters the actions of hormones that act by raising the tissue concentration of cyclic AMP. This model for the mode of action of insulin is supported by the finding that insulin also interferes with the glycogenolytic actions of adrenaline, a second hormone which acts by raising tissue cyclic AMP concentrations.
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PMID:Glucagon and insulin regulate in vitro hepatic glycogenolysis in the axolotl Ambystoma mexicanum via changes in tissue cyclic AMP concentration. 241 34

Treatment of intact hepatocytes with the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) potentiated the ability of glucagon to increase intracellular cyclic AMP concentrations. This effect was dose-dependent upon TPA, exhibiting an EC50 of 0.39 ng/ml and such activation was observed at both saturating and sub-saturating concentrations of glucagon. However, this stimulatory effect of TPA was completely abolished by the presence of the cyclic AMP phosphodiesterase inhibitor 1-isobutyl-3-methylxanthine, when TPA now inhibited the glucagon-stimulated increase in intracellular cyclic AMP concentrations. It is suggested that, as well as inhibiting glucagon-stimulated adenylate cyclase activity, TPA also inhibits cyclic AMP phosphodiesterase activity in intact hepatocytes. Treatment of either hepatocyte homogenates or purified cyclic AMP phosphodiesterase with TPA failed to show any direct inhibitory effect of TPA on activity showing that TPA did not exert any direct inhibitory action on phosphodiesterase activity. However, homogenates made from hepatocytes that had been pre-treated with TPA did show a reduced cyclic AMP phosphodiesterase activity. It is suggested that TPA might inhibit cyclic AMP phosphodiesterase activity through phosphorylation by C-kinase.
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PMID:The phorbol ester TPA inhibits cyclic AMP phosphodiesterase activity in intact hepatocytes. 243 Aug 36

Treatment of intact hepatocytes with glucagon led to the rapid desensitization of adenylate cyclase, which reached a maximum around 5 min after application of glucagon, after which resensitization ensued. Complete resensitization occurred some 20 min after the addition of glucagon. In hepatocytes which had been preincubated with the cyclic AMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), glucagon elicited a stable desensitized state where resensitization failed to occur even 20 min after exposure of hepatocytes to glucagon. Treatment with IBMX alone did not elicit desensitization. The action of IBMX in stabilizing the glucagon-mediated desensitized state was mimicked by the non-methylxanthine cyclic AMP phosphodiesterase inhibitor Ro-20-1724 [4-(3-butoxy-4-methoxylbenzyl)-2-imidazolidinone]. IBMX inhibited the resensitization process in a dose-dependent fashion with an EC50 (concn. giving 50% of maximal effect) of 26 +/- 5 microM, which was similar to the EC50 value of 22 +/- 6 microM observed for the ability of IBMX to augment the glucagon-stimulated rise in intracellular cyclic AMP concentrations. Pre-treatment of hepatocytes with IBMX did not alter the ability of either angiotensin or the glucagon analogue TH-glucagon, ligands which did not increase intracellular cyclic AMP concentrations, to cause the rapid desensitization and subsequent resensitization of adenylate cyclase. It is suggested that, although desensitization of glucagon-stimulated adenylate cyclase is elicited by a cyclic AMP-independent process, the resensitization of adenylate cyclase can be inhibited by a process which is dependent on elevated cyclic AMP concentrations. This action can be detected by attenuating the degradation of cyclic AMP by using inhibitors of cyclic AMP phosphodiesterase.
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PMID:Resensitization of hepatocyte glucagon-stimulated adenylate cyclase can be inhibited when cyclic AMP phosphodiesterase inhibitors are used to elevate intracellular cyclic AMP concentrations to supraphysiological values. 244 79

The presence of the calcium ionophore A23187 augmented glucagon's ability to elevate intracellular cyclic AMP concentrations in intact hepatocytes. However, when the cyclic AMP phosphodiesterase inhibitor 1-isobutyl-3-methylxanthine (IBMX) was added to prevent the degradation of cyclic AMP then the presence of A23187 attenuated the ability of glucagon to increase intracellular cyclic AMP concentrations. Treatment of intact hepatocytes with A23187 led to a dose-dependent persistent inhibition of the glucagon-stimulated adenylate cyclase activity expressed by a membrane fraction isolated from such ionophore-treated hepatocytes. In hepatocytes where glucagon-stimulated adenylate cyclase activity was desensitized then A23187-treatment of hepatocytes failed to exert any inhibitory action on adenylate cyclase. Treatment of isolated membranes directly with A23187 did not elicit any changes in glucagon-stimulated adenylate cyclase activity. Such actions of A23187 were blunted when Ca2+ (2.5 mM) was not added to the extracellular medium. It is suggested that treatment of hepatocytes with A23187 leads to the functional uncoupling of glucagon-stimulated adenylate cyclase activity in a manner which appears to mimic the desensitization process. A23187-treatment also exerted an overall inhibitory effect on the cyclic AMP phosphodiesterase activity displayed by intact hepatocytes. Thus treatment of hepatocytes with A23187 exerted a profound effect on cyclic AMP metabolism in these cells.
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PMID:Treatment of intact hepatocytes with the calcium ionophore A23187 perturbs both the synthesis and the degradation of the second messenger cyclic AMP. Actions on adenylate cyclase and cyclic AMP phosphodiesterase activities. 245 67

The 52 kDa subunit of the peripheral-plasma-membrane insulin-stimulated high-affinity cyclic AMP phosphodiesterase can be specifically detected by the antibody PM1 by Western-blotting procedures and also can be immunoprecipitated from a hepatocyte extract. PM1-mediated immunoprecipitation from hepatocyte extracts showed that insulin treatment of intact 32P-labelled hepatocytes caused the rapid phosphorylation of the peripheral-plasma-membrane cyclic AMP phosphodiesterase. Phosphoamino acid analysis and the use of a phosphotyrosine-specific antibody indicated that phosphorylation occurred on tyrosyl residue(s) of this phosphodiesterase. Prior treatment of hepatocytes with glucagon (10 nM) completely blocked the insulin-mediated tyrosyl phosphorylation of this 52 kDa protein, as detected with both the PM1 and the anti-phosphotyrosine antibodies. Treatment of hepatocytes with glucagon alone did not increase the phosphorylation state of the peripheral-plasma-membrane cyclic AMP phosphodiesterase. The specific anti-phosphotyrosine antibody also detected the insulin-stimulated phosphorylation of proteins of 180 kDa, 95 kDa and 39 kDa. Prior treatment of hepatocytes with glucagon decreased the ability of insulin to phosphorylate the 180 kDa and 39 kDa species, but not the 95 kDa species.
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PMID:Insulin stimulates the tyrosyl phosphorylation and activation of the 52 kDa peripheral plasma-membrane cyclic AMP phosphodiesterase in intact hepatocytes. 247 21

The mechanism whereby glucagon causes an increase in the concentration of cytoplasmic free Ca2+, [Ca2+]c, in isolated hepatocytes has been investigated. There have been proposals of cyclic-AMP-dependent and cyclic-AMP-independent mechanisms. In this work, the inactivation of pyruvate kinase was used as an indicator of increases in the activity of cyclic-AMP-dependent protein kinase, A-kinase. [Ca2+]c was measured using the fluorescent probe indo-1. The decrease in activity of pyruvate kinase caused by an increase in [Ca2+]c alone, i.e. mediated by mechanisms not involving cyclic AMP and exemplified by the effect of vasopressin, was of minimal significance under the conditions of the enzyme assay. Studies of the effects of a wide range of glucagon concentrations indicate that any increase in [Ca2+]c caused by glucagon was always associated with a decrease in pyruvate kinase activity. A similar relationship was obtained if glucagon-receptor occupancy was circumvented by using the 8-bromo-derivative of cyclic AMP to activate the A-kinase. It was also found that the cyclic AMP phosphodiesterase inhibitor isobutylmethylxanthine could potentiate the ability of glucagon to increase [Ca2+]c: no such potentiation was observed when vasopressin was used to raise [Ca2+]c. Together these data indicate that an increase in cyclic AMP concentration, sufficiently great to activate A-kinase, is a mechanism that mediates the glucagon-induced increase in [Ca2+]c.
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PMID:Evidence indicating that the glucagon-induced increase in cytoplasmic free Ca2+ concentration in hepatocytes is mediated by an increase in cyclic AMP concentration. 253 1

Treatment of intact adipocytes with either or both insulin and adrenaline stimulated membrane cyclic AMP phosphodiesterase activity only in the endoplasmic reticulum subfraction. The cyclic GMP-inhibited cyclic AMP phosphodiesterase activity was also found in this fraction. Quantitative Western blotting using a specific polyclonal antibody, raised against the homogeneous 'dense-vesicle' cyclic AMP phosphodiesterase from rat liver, identified a single 63 kDa species which was localized in the adipocyte endoplasmic reticulum fraction. The ability of adrenaline to stimulate adipocyte membrane cyclic AMP phosphodiesterase was shown to be mediated via beta-adrenoceptors and not alpha 1-adrenoceptors. Membrane cyclic AMP phosphodiesterase was stimulated by glucagon but not by vasopressin, A23187 or 12-O-tetradecanoylphorbol 13-acetate (TPA). Treatment of adipocytes with either chloroquine or dansyl cadaverine failed to affect the ability of insulin to stimulate cyclic AMP phosphodiesterase activity. Treatment of an isolated adipocyte endoplasmic reticulum membrane fraction with purified protein kinase A increased its cyclic AMP phosphodiesterase activity some 2-fold. When this fraction was treated with purified protein kinase A and [32P]ATP, label was incorporated into a 63 kDa protein which was specifically immunoprecipitated with the antiserum against the liver 'dense-vesicle' cyclic AMP phosphodiesterase.
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PMID:Subcellular localization and hormone sensitivity of adipocyte cyclic AMP phosphodiesterase. 255 12

In the study reported, colchicine, often regarded as a specific inhibitor of microtubular function, was shown to exert a concentration-dependent inhibition of the low Km cyclic AMP phosphodiesterases of the pancreatic islet, adrenal cortex and various other tissues of the rat. The results indicated that colchicine is only slightly less active as an inhibitor of the enzyme than theophylline on a molar basis and kinetic analysis revealed that both inhibitors acted competitively in the case of the liver enzyme. Our results show that the inhibitory effect of colchicine upon cyclic AMP phosphodiesterase is a general property of the alkaloid at concentrations of 5 x 10(-5)M and above in both endocrine and non-endocrine tissues. Thus, results obtained employing colchicine at concentrations significantly greater than those which are known to lead to microtubular disaggregation must be viewed with great caution if incorrect implication of microtubular participation in biological processes is to be avoided. For example, we propose that the previously reported paradoxical stimulatory effects of colchicine on the secretion of glucagon from the rat pancreatic islet and on steroidogenesis in the rat adrenal may be due to cyclic AMP accumulation consequent upon phosphodiesterase inhibition in these endocrine tissues and not to microtubular disaggregation as has hitherto been assumed.
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PMID:Inhibition of adenosine 3',5'-cyclic monophosphate phosphodiesterase by colchicine: implications for glucagon and corticosteroid secretion. 283 8

The phorbol ester TPA (12-O-tetradecanoyl phorbol-13-acetate) causes a dose-dependent inhibition of the glucagon-stimulated adenylate cyclase activity expressed in plasma membranes isolated from TPA-treated hepatocytes. However, no observable inhibitory effect of TPA on adenylate cyclase activity was observed in cells which had been exposed to glucagon for 5 min, prior to isolation, to desensitise adenylate cyclase. The degree of inhibition of adenylate cyclase elicited by both glucagon desensitisation and TPA treatment of hepatocytes was identical. Pre-treatment of hepatocytes with TPA was also found to prevent glucagon from blocking insulin's activation of the peripheral plasma membrane cyclic AMP phosphodiesterase in intact hepatocytes. TPA treatment also inhibited the ability of cholera toxin to activate the peripheral cyclic AMP phosphodiesterase in intact hepatocytes. It is suggested that in these particular instances TPA and glucagon elicit mutually exclusive processes rather than TPA mimicking glucagon desensitisation per se.
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PMID:The phorbol ester TPA prevents the expression of both glucagon desensitisation and the glucagon-mediated block of insulin stimulation of the peripheral plasma membrane cyclic AMP phosphodiesterase in rat hepatocytes. 299 Oct 13

Treatment of hepatocytes with islet activating protein (pertussis toxin) from Bordetella pertussis blocked the ability of insulin to inhibit adenylate cyclase activity both in broken plasma membranes and in intact hepatocytes. Such treatment of intact hepatocytes with pertussis toxin did not prevent insulin from activating the peripheral plasma membrane cyclic AMP phosphodiesterase although it did inhibit the ability of insulin to activate the 'dense-vesicle' cyclic AMP phosphodiesterase. The ability of glucagon pretreatment of hepatocytes to block insulin's activation of the plasma membrane cyclic AMP phosphodiesterase was abolished in pertussis toxin-treated hepatocytes. It is suggested that the ability of insulin to manipulate cyclic AMP concentrations by inhibiting adenylate cyclase and activating the plasma membrane and 'dense-vesicle' cyclic AMP phosphodiesterases involves interactions with the guanine nucleotide regulatory protein system occurring in liver plasma membranes.
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PMID:The action of islet activating protein (pertussis toxin) on insulin's ability to inhibit adenylate cyclase and activate cyclic AMP phosphodiesterases in hepatocytes. 301 98


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