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 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

Pretreatment of cultured rat hepatocytes with dexamethasone markedly enhanced the acute cAMP response to glucagon, isoproterenol or forskolin. The effect of dexamethasone was apparent within 3-6 hr and was maximal after 20-30 hr. The amplification of the cAMP response to glucagon could also be produced by other glucocorticoids, with relative potency dexamethasone much greater than methylprednisolone greater than hydrocortisone. The increased cAMP response was associated with a reduced cAMP phosphodiesterase activity in cell lysates and a reduced effect of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine in intact cells, indicating that the glucocorticoid pretreatment reduced cAMP degradation. However, the increase in response to glucagon in glucocorticoid-treated cells was relatively larger than the increase in forskolin response and also larger than the decrease in phosphodiesterase activity, suggesting that other factors in addition to down-regulation of phosphodiesterases was responsible for the effect. Cycloheximide abolished the difference in phosphodiesterase activity and cAMP response between dexamethasone-treated and control cells. The results suggest that the glucocorticoids increase the ability of hepatocytes to accumulate cAMP due to protein synthesis-dependent processes which at least in part involve reduced degradation of cAMP.
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PMID:Studies of glucocorticoid enhancement of the capacity of hepatocytes to accumulate cyclic AMP. 247 93

Insulin sensitive phosphodiesterase from rat adipocytes is found in particulate fractions. Solubilisation of the enzyme with triton X-100 yields a preparation containing more than one phosphodiesterase activity as judged by its rate of thermal denaturation at 45 degrees C and by its non-linear kinetic plots. Immunoprecipitation of solubilised activity with a polyclonal antiserum raised against purified insulin-sensitive rat liver phosphodiesterase selected a form of the enzyme which showed a single exponential decay of enzyme activity when heated at 45 degrees C and linear low Km kinetics. Treatment of adipocytes with insulin ACTH, glucagon or isoproterenol stimulated the low Km particulate phosphodiesterase. The hormonal activation was retained following solubilisation and was also seen when activity was immunoprecipitated. It is suggested that all four hormones activate the same form of phosphodiesterase.
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PMID:Insulin and lipolytic hormones stimulate the same phosphodiesterase isoform in rat adipose tissue. 254 76

Incubation of a hepatocyte particulate fraction with ATP and the isolated catalytic unit of cyclic AMP-dependent protein kinase (A-kinase) selectively activated the high-affinity 'dense-vesicle' cycle AMP phosphodiesterase. Such activation only occurred if the membranes had been pre-treated with Mg2+. Mg2+ pre-treatment appeared to function by stimulating endogenous phosphatases and did not affect phosphodiesterase activity. Using the antiserum DV4, which specifically immunoprecipitated the 51 and 57 kDa components of the 'dense-vesicle' phosphodiesterase from a detergent-solubilized membrane extract, we isolated a 32P-labelled phosphoprotein from 32P-labelled hepatocytes. MgCl2 treatment of such labelled membranes removed 32P from the immunoprecipitated protein. Incubation of the Mg2+-pre-treated membranes with [32P]ATP and A-kinase led to the time-dependent incorporation of label into the 'dense-vesicle' phosphodiesterase, as detected by specific immunoprecipitation with the antiserum DV4. The time-dependences of phosphodiesterase activation and incorporation of label were similar. It is suggested (i) that phosphorylation of the 'dense-vesicle' phosphodiesterase by A-kinase leads to its activation, and that such a process accounts for the ability of glucagon and other hormones, which increase intracellular cyclic AMP concentrations, to activate this enzyme, and (ii) that an as yet unidentified kinase can phosphorylate this enzyme without causing any significant change in enzyme activity but which prevents activation and phosphorylation of the phosphodiesterase by A-kinase.
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PMID:Activation and phosphorylation of the 'dense-vesicle' high-affinity cyclic AMP phosphodiesterase by cyclic AMP-dependent protein kinase. 254 54

The present studies were undertaken to characterize further the influence of synthetic human beta-endorphin (0.5 mg/h) on insulin and glucagon responses to intravenous glucose in humans. Infusion of beta-endorphin in 10 normal volunteers caused a clear-cut inhibition of the overall insulin responses to a glucose pulse (0.33 g/kg iv) with values of glucose disappearance rates in the diabetic range [0.89 +/- 0.09 (P less than 0.01) vs. saline 1.82 +/- 0.15%/min]. Glucose-induced glucagon suppression was significantly lower during beta-endorphin, a fact that could have contributed to the reduced glucose utilization rates. The infusion of theophylline (150 mg + 350 mg/h) to increase the intracellular cAMP activity by inhibiting phosphodiesterase completely reversed the inhibitory effect of beta-endorphin on glucose-induced insulin secretion. As a consequence, glucose disappearance rates rose to 1.77 +/- 0.18%/min. Theophylline did not influence significantly the glucagon-releasing effect of beta-endorphin as well as the reduced glucagon suppression. An infusion of exogenous calcium (100 mg as iv bolus + 5 mg/min) to raise serum calcium in the hypercalcemic range (15 mg/dl) and lysine acetylsalicylate (72 mg/min) to block the synthesis of endogenous prostaglandin E did not interfere with the inhibiting effect of beta-endorphin on insulin secretion. These data confirm that beta-endorphin stimulates glucagon and inhibits basal and glucose-stimulated insulin secretion and suggest that the opioid influences the intraislet adenylate cyclase activity.
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PMID:Beta-endorphin and islet hormone release in humans: evidence for interference with cAMP. 255 Nov 76

To elucidate in vitro the transience of glucagon-induced hepatic glucose release, the effects of glucagon on hepatic glucose production and cAMP release were evaluated in the isolated rat liver preparation perfused by a nonrecirculating system. Glucagon was added to the infusate in stepwise increasing concentrations at 0, 60, and 100 min to give final concentrations of 2.5 X 10(-11), 10(-9), and 5 X 10(-8) M, respectively. Glucagon at 2.5 X 10(-11) M caused cAMP release [basal (mean +/- SD), 11.2 +/- 3.0 pmol/(min X 100 g BW)] to rise rapidly and plateau at 23.3 +/- 7.0 pmol/(min X 100 g BW), whereas hepatic glucose production [basal, 3.7 +/- 1.6 mumol/(min X 100 g BW)] increased only transiently to a maximum of 15.3 +/- 3.1 mumol/(min X 100 g BW) and fell thereafter. The enhanced cAMP release during the consecutive glucagon infusion was accompanied by a transient rise in hepatic glucose production during the second, but not during a third, glucagon infusion. When 3-isobutyl-1-methylxanthine, a potent phosphodiesterase inhibitor, was added to the perfusion medium (0.5 mM), the cAMP response to 2.5 X 10(-11) M glucagon was enhanced [247 +/- 124 pmol/(min X 100 g BW)] as was hepatic glucose production (+ 21%; P less than 0.05). Further augmentation of the glucagon concentration was followed by an increase in hepatic cAMP, but not glucose, release. When glucagon infusion (2.5 X 10(-11) M) was repeated with a glucagon-free period of 30 min in between, no stimulation of cAMP and consecutive glucose release was found during the second period. However, when the second glucagon dose was increased to 10(-9) M, glucose and cAMP release were again stimulated to the same extent as in experiments with no glucagon-free period in between. We conclude that the size of the glycogen pool and the cAMP concentration directly modulate hepatic glucose production and are responsible for evanescent glucagon action. This mechanism can be described by computer simulation.
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PMID:Contribution by the glycogen pool and adenosine 3',5'-monophosphate release to the evanescent effect of glucagon on hepatic glucose production in vitro. 257 52

Forskolin, a direct activator of adenylate cyclase, stimulates cAMP production in islet cells. The effects of forskolin on the release of somatostatin, glucagon, and insulin were studied using the isolated, perfused dog pancreas. It was found that concentrations ranging from 0.075 microM-1 microM stimulated the secretion of somatostatin, glucagon, and insulin in a dose-related manner. The effects of 0.15 microM and of 0.6 microM forskolin were modulated by the prevailing glucose level with higher D and B and lower A cell responses at high (11 mM) than at low (2.8 mM) or zero glucose. In the absence of extracellular Ca++, forskolin (1 microM) possessed no stimulatory effect on pancreatic hormone secretion. Perfusion of 1 microM atropine, 1 microM propranolol, and 1 microM phentolamine had no effect on forskolin-mediated (0.3 microM) hormone output from pancreas. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (25 microM) elicited qualitatively similar hormone response to forskolin. In conclusion, the experiments demonstrate that forskolin is a potent, reversible, stimulus of pancreatic hormone secretion. Its effects are apparently not mediated via the sympathetic or parasympathetic nerve endings in pancreas. Forskolin may prove to be a valuable pharmacological tool in probing the role of the adenylate cyclase-cAMP system in pancreatic hormone secretion.
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PMID:Forskolin, an activator of adenylate cyclase, stimulates pancreatic insulin, glucagon, and somatostatin release in the dog: studies in vitro. 258 71

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 effects of aging and of food restriction at different times during life on rat adipocyte responses to glucagon and epinephrine were explored by studying hormone-stimulated lipolysis, hormone binding, and phosphodiesterase activity. The times of food restriction were: (a) from 6 weeks of age, (b) limited to early life, and (c) beginning in young adult life. Hormone-sensitive lipolysis is lost with age. Food restriction from 6 weeks of age prevents this loss, and food restriction started in adult life causes the recovery of this lipolysis. Hormone binding studies reveal that: (a) changes in glucagon-stimulated lipolysis parallel changes in glucagon binding; (b) glucagon binding and glucagon-stimulated lipolysis correlate inversely with cell size; (c) changes in epinephrine-stimulated lipolysis are not due to changes in beta-adrenergic binding; and (d) neither beta-adrenergic binding nor epinephrine-promoted lipolysis correlate with fat cell size. Phosphodiesterase activity is not influenced by diet, making it unlikely to be a postreceptor component lost with age.
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PMID:Action of food restriction on age-related changes in adipocyte lipolysis. 282 98

In isolated hepatocytes, quinacrine (150-250 microM) inhibited vasopressin-induced increases in glucose release, glycogen phosphorylase a activity and 45Ca2+ efflux; and glucagon-induced increases in glucose release and cyclic AMP formation. These results indicate that a phospholipase A2 enzyme sensitive to quinacrine is unlikely to be involved in the process by which vasopressin stimulates glycogen phosphorylase activity in the liver cell. In cells labelled with [3H]inositol, much lower concentrations of quinacrine (20-50 microM) inhibited the stimulation by vasopressin of the accumulation of [3H]inositol. The drug had little effect on vasopressin-induced accumulation of [3H]inositol mono-, bis- and tris-phosphates. In the absence of vasopressin, higher concentrations of quinacrine caused a small stimulation of glycogen phosphorylase activity, 45Ca2+ release and the formation of [3H]inositol polyphosphates. Quinacrine did not inhibit the degradation by liver homogenates of inositol 1-phosphate, inositol 4,5-bisphosphate or inositol 1,4,5-trisphosphate. It is concluded that concentrations of quinacrine comparable with those which inhibit phospholipase A2 [G.J. Blackwell, W.G. Duncombe, R.J. Flower, M.F. Parsons and J.R. Vane, Br. J. Pharmac. 59, 353-366 (1977)] inhibit the stimulation by vasopressin of inositol utilization without significantly affecting coupling between hormone receptors and adenyl cyclase or phosphoinositide-specific phosphodiesterase, the action of the phosphodiesterase, and the degradation of inositol triphosphate.
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PMID:Effects of quinacrine on vasopressin-induced changes in glycogen phosphorylase activity, Ca2+ transport and phosphoinositide metabolism in isolated hepatocytes. 282 12


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