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)

Pulsatile administration of glucagon to perifused rat hepatocytes stimulates hepatocyte glucose production (HGP) more effectively than continuous administration. Having established that this effect was due to delayed relaxation of glucagon-stimulated HGP (t1/2 for decay = 3.54 +/- 0.60 min) we wished to examine the mechanism of response termination. Delayed dissociation of glucagon from its receptor was excluded by the brisk washout of [125I]glucagon from perifusion columns (t1/2 = 1.00 +/- 0.13) and the rapid decay in glucagon-stimulated cAMP released into the perifusion medium (t1/2 = 1.14 +/- 0.12). The relaxation of the HGP response to a pulse of administered cAMP was comparable to the decay in glucagon-stimulated HGP (t1/2 = 3.28 +/- 0.22). Furthermore, the phosphodiesterase inhibitor isobutyl-methylxanthine did not alter the decay of the HGP response to glucagon despite increasing the amplitude of the response (t1/2 = 3.04 +/- 0.36). These data place the rate-limiting step for HGP relaxation distal to cAMP generation and degradation. The decay of the beta-hydroxybutyrate response to a glucagon pulse was not different from the cAMP response (t1/2 = 1.14 +/- 0.23), whereas the decay of gluconeogenesis from lactate was not significantly different from HGP relaxation (t1/2 = 1.94 +/- 0.08). We conclude that rate-limiting events for HGP relaxation occur distal to the second messenger cascade; however, ketogenesis is more closely coupled to the kinetics of cAMP. These results may help to explain the absence of excessive ketosis during fasting in normal humans, who secrete glucagon episodically at 10- to 14-min intervals.
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PMID:A kinetic analysis of hepatocyte responses to a glucagon pulse: mechanism and metabolic consequences of differences in response decay times. 243 20

Membrane currents were recorded from voltage-clamped Xenopus laevis oocytes, surrounded by their enveloping follicular and epithelial cells. Porcine vasoactive intestinal peptide (VIP) generated a membrane current due to an increase in membrane conductance to K+. The VIP current was mimicked by the adenylate cyclase activator forskolin and was potentiated by phosphodiesterase inhibitors, suggesting that adenosine 3',5'-cyclic monophosphate (cyclic AMP) plays a role in mediating the response. Though resembling the follicle's responses to catecholamines and adenosine in ionic basis and apparent mechanism, the response to VIP was not blocked by catecholaminergic or purinergic antagonists, indicating the presence of a specific VIP receptor in the follicle. Among the VIP related peptides, PHM-27 generated similar but smaller K+ currents and porcine secretin and glucagon neither elicited a response nor blocked that to VIP. After treating follicles with collagenase to remove the epithelial and follicular cells the responses to VIP were either substantially reduced or abolished, suggesting that the VIP receptors and K+ channels are both located in the follicular cells.
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PMID:Membrane currents elicited by porcine vasoactive intestinal peptide (VIP) in follicle-enclosed Xenopus oocytes. 244 88

Glucagon increases the cytoplasmic free calcium concentration as measured by aequorin bioluminescence. It has been proposed by Wakelam et al. (Nature 323 (1986) 68-71) that low concentrations of glucagon mobilize calcium from an intracellular pool by causing polyphosphoinositide breakdown. To identify whether cyclic AMP mediates changes in the cytoplasmic free calcium concentration ([Ca2+]c) induced by glucagon, the effects of forskolin and exogenous cyclic AMP on [Ca2+]c were compared with that of glucagon in aequorin-loaded hepatocytes. Although the magnitudes of the [Ca2+]c responses to 250 microM forskolin and 1 mM 8-bromo cyclic AMP were identical to that of 5 nM glucagon, these two agents induced a more prolonged elevation of [Ca2+]c. Glucagon-induced elevation of [Ca2+]c was accompanied by a smaller increase in cyclic AMP than that induced by forskolin. When the cyclic AMP response to glucagon was potentiated by an inhibitor of phosphodiesterase, 3-isobutyl-1-methylxanthine, the glucagon-induced increase in [Ca2+]c was not affected. Conversely, when the cyclic AMP response to glucagon was reduced by pretreatment of the cells with angiotensin II, glucagon-induced changes in [Ca2+]c were rather enhanced. Furthermore, vasopressin potentiated glucagon-induced changes in [Ca2+]c despite the reduction of the cyclic AMP response to glucagon. In the presence of 1 microM extracellular calcium, angiotensin II did not enhance glucagon-induced changes in [Ca2+]c. These results suggest that at least part of the action of 5 nM glucagon on calcium mobilization is independent of cyclic AMP.
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PMID:Evidence of cyclic AMP-independent action of glucagon on calcium mobilization in rat hepatocytes. 245 73

Elevation of cyclic AMP (cAMP) content in perfused rat hearts by exposure to glucagon, forskolin, and 1-methyl-3-isobutylxanthine (IBMX) increased rates of protein synthesis during the second hour of perfusion with buffer that contained glucose in the absence of added insulin. When tetrodotoxin was added to arrest contractile activity, glucagon, forskolin, and IBMX still elevated cAMP content and rates of protein synthesis. Perfusion of beating rat hearts at elevated aortic pressure (120 mm Hg vs. 60 mm Hg) also accelerated rates of protein synthesis and raised cAMP content and cAMP-dependent protein kinase activity during the second hour of perfusion. Insulin accelerated rates of protein synthesis in beating hearts during the first and second hour of perfusion but did not increase cAMP content. Elevation of aortic pressure in insulin-treated hearts raised cAMP content but had no further effect on rates of protein synthesis. Perfusion of arrested hearts for as little as 2 minutes at 120 mm Hg resulted in a rapid and sustained increase in cAMP content, cAMP-dependent protein kinase activity, and rate of protein synthesis after 60-120 minutes of additional perfusion at 60 mm Hg. Exposure of arrested hearts to 0.2 mM methacholine, a muscarinic-cholinergic agonist, for 5 minutes before elevation of perfusion pressure blocked the pressure-induced increases in cAMP content, cAMP-dependent protein kinase activity, and rates of protein synthesis. When hearts were removed from pertussis toxin-treated animals, methacholine did not block the effects of forskolin on these same three parameters. These studies indicated that elevation of tissue cAMP by hormone binding, direct activation of adenylate cyclase, or inhibition of phosphodiesterase resulted in acceleration of protein synthesis. Furthermore, the effects of increased aortic pressure to accelerate synthesis appeared to involve a cAMP-dependent mechanism that was independent of changes in contractile activity but could be blocked with a muscarinic-cholinergic agonist. Acceleration of protein synthesis by insulin was not associated with an elevation of cAMP.
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PMID:Increased cyclic AMP content accelerates protein synthesis in rat heart. 247 73

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


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