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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of heparin on the renal adenylate cyclase (AC)/cyclic adenosine monophosphate (cAMP) system was studied in vitro in renal cortical membrane preparations and in vivo on hormone-stimulated nephrogenous cAMP excretion. The heparin dose dependently inhibited basal and hormone-stimulated rat renal cortical AC activity. The heparin concentration causing 50% inhibition was 45 micrograms/ml for the basal activity and 33 and 85 micrograms/ml for the parathyroid hormone (PTH) and glucagon-stimulated activities, respectively. PTH- and glucagon-stimulated AC activity was inhibited by the non-antithrombotic heparinoid, N-acetylated N-disulfated heparin, but not by a structural analogue of heparin, dextran sulfate. Forskolin- and Mn2(+)-stimulated AC activity was also inhibited by heparin, while NaF stimulated activity was resistant to it. Increasing Mg2+ concentration did not affect the inhibition of basal and PTH-stimulated AC activity by heparin. The urinary excretion of nephrogenous cAMP was determined in parathyroidectomized rats treated with glucagon (group 1), glucagon and heparin (group 2), heparin alone (group 3) and control (group 4). Glucagon induced a significant increase in nephrogenous cAMP excretion. The urinary excretion of nephrogenous cAMP, however, was significantly lower in group 2 (receiving glucagon and heparin) than in group 1 (receiving glucagon alone). There were no significant changes in nephrogenous cAMP in groups 3 and 4. These results suggest that heparin is a potent inhibitor of renal AC in vivo and in vitro. Taken together, our data point out the catalytic unit of the AC system as the site of heparin interaction.
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PMID:Effect of heparin on cortical adenylate cyclase activity and on urinary excretion of 3',5'-adenosine monophosphate in rat. 248 35

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 roles of calcium, cyclic AMP (cAMP), activation of protein kinase C (PKC) and the effect of ATP on glucagon secretion were investigated in intact and permeabilized rat islets of Langerhans, Ca2+ (10 nM-10 microM) stimulated glucagon secretion from electrically permeabilized islets in a dose-dependent manner. Forskolin and cAMP stimulated secretion from intact and permeabilized islets respectively, the latter at both sub-stimulatory (50 nM) and stimulatory (10 microM) Ca2+ concentrations. The tumour-promoting phorbol ester phorbol 12-myristate 13-acetate (PMA) increased secretion from both intact and permeabilized islets. In the latter, PMA increased glucagon release at both Ca2+ concentrations, the effect being enhanced at the stimulatory Ca2+ concentration, over and above that caused by Ca2+ alone. Reduction of ATP content by incubation with the metabolic inhibitor 2,4-dinitrophenol resulted in an increased basal release of glucagon from intact islets, whilst arginine-induced glucagon secretion was abolished in both intact and permeabilized islets. Ca2+-induced glucagon secretion required MgATP in the permeabilized islets of Langerhans. These results suggest that Ca2+ acts as an initiator of glucagon secretion, whilst cAMP and activation of PKC may exert their effect as modulators of secretion. ATP is required for glucagon secretion in electrically permeabilized islets and is necessary for arginine-induced glucagon secretion in both intact and permeabilized islets.
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PMID:Role of intracellular mediators in glucagon secretion: studies using intact and electrically permeabilized rat islets of Langerhans. 285 94

We have evaluated the potential of the clonal insulin-secretory cell line HIT-T15 as a model system for investigating stimulus-secretion coupling in pancreatic B cells. In contrast to other cell lines, HIT cell insulin secretion was consistently stimulated 2- to 3-fold by D-glucose. The maximally effective concentration of glucose was 10 mmol/l; between 2 and 10 mmol/l glucose the increase in insulin release was paralleled by an increased rate of glucose oxidation. The main characteristics of glucose-stimulated insulin release by HIT cells were essentially similar to those of normal islets. Thus, the response was specific for metabolizable sugars (D-mannose and D-glyceraldehyde stimulated insulin release but L-glucose and D-galactose were ineffective); markedly dependent on extracellular Ca2+ concentration; potentiated by forskolin, glucagon, acetylcholine and 12-O-tetradecanoyl phorbol 13-acetate; inhibited by adrenaline or somatostatin; showed a biphasic pattern of release in perifusion experiments, with both phases being potentiated by forskolin. The secretory response of the HIT cells to amino acids was also similar to that of normal islets. Thus, L-leucine and its deamination product 2-ketoisocaproate were effective stimuli, whereas L-isoleucine and L-glutamine were ineffective. Insulin release from HIT cells could also be evoked by the sulphonylureas glibenclamide and tolbutamide and by an increase in concentration of extracellular K+ to 40 mmol/l. The content of cyclic AMP in HIT cells was increased modestly by glucose but not by an increase in extracellular K+. Forskolin elicited a 4-fold increase in cyclic AMP content. We conclude that HIT cells retain the essential features of the insulin secretory response of normal B cells and represent an important tool for further biochemical characterization of the secretory system.
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PMID:Insulin secretory responses of a clonal cell line of simian virus 40-transformed B cells. 302 78

This study demonstrates that the threshold of glucose-stimulated insulin secretion can be regulated in vivo by long term hormonal and nutrient modifications. The sensitivity of the pancreatic B-cell to glucose stimulation was determined by examining the pattern of insulin release from pancreases perfused with linear glucose gradients. Male rats infused with ovine PRL for 4 days and rats receiving five hourly injections of glucose had a lower threshold and enhanced rates of insulin release at all stimulatory glucose concentrations. Infusion of bGH for 4 days was without effect on glucose gradient-stimulated insulin release. Fasting the rats for 48 h resulted in an elevation of the threshold and a substantial reduction in the extent of insulin release. To determine possible processes involved in these long term modifications of the threshold of glucose-stimulated insulin secretion, the in vitro effect of potentiators of insulin release was examined. Forskolin, glucagon, cholecystokinin, and carbamylcholine were able to lower the threshold and increase the extent of insulin release. This suggests that the long term regulation of insulin secretion may modulate processes controlling cAMP concentrations and the hydrolysis of phosphoinositides in pancreatic B-cells. Also, the proposed incretin gastric inhibitory polypeptide was capable of lowering the threshold and increasing insulin secretion at stimulatory glucose concentrations. The consequences of a decreased threshold is a markedly enhanced insulin secretion at normal serum glucose concentrations.
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PMID:Nutrient and hormonal regulation of the threshold of glucose-stimulated insulin secretion in isolated rat pancreases. 304 73

The binding of [14,15-3H]14,15-dihydroforskolin ([3H]DHF) to rat liver membranes has been further characterized and was compared with the stimulatory effect of forskolin on adenylate cyclase. The binding equilibrium dissociation constant (KD) for 14,15-dihydroforskolin obtained in inhibition experiments was 0.6 microM, with a maximal binding capacity (Bmax) of 114 pmol/mg protein. A similar KD value (0.5 microM) was derived from kinetics studies that revealed very rapid association and dissociation reactions. For structure-activity relationship studies several forskolin derivatives were synthesized and tested for their ability to inhibit [3H]DHF binding and increase adenylate cyclase activity. Among the tested compounds, forskolin itself was the most potent agonist (K1 = 0.2 microM). Further modification of the molecule in position 7 and (or) 1 decreased or abolished its agonist properties in both adenylate cyclase and binding studies. [3H]DHF binding was not affected by several nucleotides, carbohydrates, lectins, and hormone receptor agonists including isoproterenol, glucagon, and adenosine, but the steroids 17-beta-estradiol, progesterone, and testosterone showed slight inhibitory effects at unphysiologically high concentrations. [3H]DHF binding and forskolin-stimulated adenylate cyclase were sensitive to heat and N-ethylmaleimide treatment. Forskolin protected adenylate cyclase against inactivation by heat but not by N-ethylmaleimide. Preincubation of the membrane with trypsin decreased [3H]DHF binding. The results presented in this study demonstrate that the binding sites identified with [3H]DHF have a high specificity for forskolin and provide evidence that these binding sites are involved in the stimulation of adenylate cyclase by forskolin.
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PMID:Binding of [14,15-3H]14,15-dihydroforskolin to rat liver membranes: comparison with the stimulatory effect of forskolin on adenylate cyclase. 362 Oct 43

[1-N alpha-Trinitrophenylhistidine,12-homoarginine]glucagon (THG) is a potent antagonist of the effects of glucagon on liver membrane adenylate cyclase. In isolated hepatocytes, this glucagon analogue was an extremely weak partial agonist for cAMP accumulation, and it blocked the stimulation of cAMP accumulation produced by glucagon. However, THG was a full agonist for the stimulation of glycogenolysis, gluconeogenesis and urea synthesis in rat hepatocytes, and did not antagonize the metabolic effects of glucagon under most of the conditions examined. Forskolin potentiated the stimulation of cAMP accumulation produced by glucagon or THG, but did not potentiate their metabolic actions. A much larger increase in cAMP levels seemed to be required for the stimulation of hepatocyte metabolism by forskolin than by glucagon or THG. This may suggest the existence of a functional compartmentation of cAMP in rat hepatocytes. The possible existence of compartments in cAMP-mediated hormone actions and the involvement of factors, besides cAMP, in mediating the effects of THG and glucagon is suggested.
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PMID:Metabolic effects and cyclic AMP levels produced by glucagon, (1-N alpha-Trinitrophenylhistidine,12-homoarginine)glucagon and forskolin in isolated rat hepatocytes. 608 25

Both forskolin and ethanol elicit the activation of basal and ligand-stimulated adenylate cyclase activities in rat liver plasma membranes. Ethanol is most potent at activating the fluoride- and glucagon-stimulated activities whilst having little effect on basal activity. In contrast forskolin exerts its greatest effect on basal activity. Over the concentration range that ethanol activates adenylate cyclase, it also increases bilayer fluidity as indicated by a decrease in the values of the order parameters for an incorporated fatty acid spin probe. At high concentrations forskolin does increase bilayer fluidity. However, it only begins to do so at concentrations above those where forskolin has already exerted its maximal effect in activating adenylate cyclase. Forskolin can still activate, albeit to a reduced extent, detergent-solubilized adenylate cyclase whereas ethanol cannot. Forskolin elicits a pronounced rise in hepatocyte intracellular cyclic AMP concentrations, whereas ethanol does not. Both forskolin and ethanol reduce the temperature of onset of the lipid phase separation occurring in rat liver plasma membranes. This is detected in Arrhenius plots of both glucagon-stimulated adenylate cyclase activity and order parameters of an incorporated fatty acid spin probe, where we find that forskolin is particularly potent in decreasing the temperature at which this lipid phase separation occurs. Our results are consistent with the notion that forskolin exerts its effect on adenylate cyclase primarily by a direct action on the catalytic unit of the enzyme. However, as forskolin is a potent perturber of the organisation of the lipid bilayer it is possible that this could modulate its effect on adenylate cyclase and might be expected to affect the activity of other membrane enzymes.
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PMID:Forskolin and ethanol both perturb the structure of liver plasma membranes and activate adenylate cyclase activity. 630 64

The effects of the photoreactive GTP analogue GTP-gamma-azidoanilide on rat liver plasma-membrane adenylate cyclase are described. U.v. irradiation in the presence of the analogue abolished activation by any effector or combination of effectors that function via the activatory G protein. Partial protection against this inhibition was given by F- and guanosine 5'-[gamma-thio]triphosphate. It is concluded that GTP-gamma-azidoanilide acts by a light-induced covalent reaction with the G protein. In the dark the effects of the analogue were similar to those of GTP. Irradiation in the presence of GTP-gamma-azidoanilide was found to reduce but not to abolish activation of rat liver plasma membrane adenylate cyclase by forskolin. The activation by forskolin and GTP together were greater than the sum of the individual activations. Forskolin doubled adenylate cyclase activity in the presence of glucagon and guanosine 5'-[beta, gamma-imido]triphosphate, which might be expected to activate to the maximum possible extent via the G protein. It is concluded that there are two components to the forskolin activation, a guanine nucleotide-dependent and a guanine nucleotide-independent component.
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PMID:The role of a guanine nucleotide-binding protein in the activation of rat liver plasma-membrane adenylate cyclase by forskolin. 632 Jul 98

The effects of forskolin on rat liver plasma membrane adenylyl cyclase were studied. The diterpene stimulated the Vmax of the enzyme system with apparent Km values of 3-5 microM. Stimulations were marked both in the absence (20-fold over control) as well as in the presence of various stimulators such as GTP, GuoPP[NH]P, NaF alone or in combination with glucagon. Except with GTP, where stimulations of activities by forskolin and the nucleotide were synergistic (more than additive), stimulations of combinations of GuoPP[NH]P, NaF or glucagon with forskolin were additive. Forskolin did not alter significantly the apparent Km values of the enzyme for MgATP or MnATP or the apparent Ka values (concentrations giving stimulations that are 50% of maximum) for Mg or Mn ions, GTP, GuoPP[NH]P or NaF. Forskolin caused a decrease in the concentration of glucagon required for half-maximal stimulation from 5 microM to 1.5 microM. Except for this effect on the Ka for the glucagon, the only kinetic parameter altered was the Vmax under all conditions tested. Although proteolysis stimulated liver membrane adenylyl cyclase under control conditions, it did not enhance forskolin-stimulated activities. More extensive proteolysis, which resulted in decreased activities in the absence of forskolin, also resulted in reduced forskolin-stimulated activities. 'Uncoupling' of the guanine-nucleotide-binding regulatory component, that mediates guanine nucleotide stimulation by addition of 30 mM MnCl2, did not result in 'uncoupling' of forskolin stimulation. The data indicate that the diterpene forskolin stimulates adenylyl cyclase activity by a novel mechanism that differs from that by which NaF or guanylyl nucleotides affect this membrane-bound system and that the diterpene should be a useful tool with which to explore as yet unrecognized modes of regulation of cyclic AMP production.
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PMID:Forskolin regulation of liver membrane adenylyl cyclase. 660 28


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