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)

1. Adenylate cyclase (EC 4.6.1.1) activity was characterized in human liver, and its subcellular distribution compared with that of three other potential enzyme markers of the pericellular membrane: leucine aminopeptidase (EC 3.4.11.1), gamma-glutamyltransferase (EC 2.3.2.2) and 5'-nucleotidase (EC 3.1.3.5). Although these three enzyme activities were detected in each of the subcellular fractions studied, 85% of the total adenylate cyclase activity was found in the 1000 g pellet ('nuclear' fraction) with a threefold increase in specific activity as compared with the homogenate. No adenylate cyclase activity existed in the 150 000 g supernatant fraction. 2. In the 'nuclear' fraction, adenylate cyclase activity was increased in a dose-dependent fashion by glucagon with a half-maximal stimulation at 10 nmol/l and a maximal four- to seven-fold increase at 1 mumol/l. Catecholamines activated adenylate cyclase 2.5- to three-fold, with an order of potency (protokylol greater than isoprenaline greater than adrenaline greater than noradrenaline) typical of a beta 2-adrenoreceptor. Prostaglandin E1 and NaF also stimulated cyclase two- and four-fold respectively. Insulin, serotonin, dopamine, thyroid-stimulating hormone and ACTH had no effect. Adenosine provoked a weak inhibition at 0.1 mmol/l. Finally guanosine triphosphate and 5'-guanylyl imidodiphosphate induced a marked increase in basal activity, four- and eight-fold respectively, but both reduced the relative increase in enzyme activity due to glucagon or adrenaline. 3. Cyclase from foetal liver (12--16 weeks old) and cirrhotic adult liver appeared to behave similarly to that from normal liver; however, foetal cyclase was more active, and cirrhotic enzyme less active than normal adult liver. Both systems responded to catecholamines via a beta 2-adrenoreceptor. 4. These results validate the use of rat liver adenylate cyclase as a tool for pharmacological and physiological studies.
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PMID:The adenylate cyclase system in human liver: characterization, subcellular distribution and hormonal sensitivity in normal or cirrhotic adult, and in foetal liver. 4 65

When glucagon release from monolayer cultures of newborn rat pancreas was measured over four hours in media containing 2.5 mM Ca++, a significant cyclic AMP-related inhibition of release was observed. This was noted whether intracellular cyclic AMP levels were raised by the addition of exogenous cyclic AMP or dibutyryl cyclic AMP, by phosphodiesterase inhibition with theophylline, or by the stimulation of adenylate cyclase with cholera toxin. The inhibition was concentration dependent for cyclic AMP and could not be reproduced by the addition of AMP, ADP or ATP. Adenosine also inhibited glucagon release while ATP was stimulatory. From time course studies it appeared that the inhibitory effects of cyclic AMP and cholera toxin were progressive after two hours of incubation. With cholera toxin an early stimulation of glucagon release was observed. The effects of cyclic AMP and cholera toxin on arginine-stimulated glucagon release were to stimulate further the glucagon release during the first hour of the incubation. Thus, the effects of raising intracellular cyclic AMP levels were biphasic in that both an early stimulation and a late inhibition of glucagon release were observed. In examining the nature of these responses a remarkable controlling role for Ca++ was uncovered: at Ca concentrations of 0.3 mM and lower no effect of cyclic AMP on glucagon release was found. With 1 mM Ca++ in the medium cyclic AMP stimulated glucagon release early (30 min) and thereafter had no further effect. In the presence of 2.5 mM Ca++ cyclic AMP did not stimulate early but did cause the delayed inhibition of release. It is concluded that the effect of cyclic AMP on glucagon release can be either stimulatory or inhibitory depending upon the Ca++ concentration of the medium and the duration of exposure to raised cyclic AMP levels.
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PMID:Stimulatory and inhibitory effects of cyclic AMP on pancreatic glucagon release from monolayer cultures and the controlling role of calcium. 18 8

The production of adenosine 3',5'-monophosphate (cyclic AMP) in a membrane preparation from human liver homogenate has been studied. Cyclic AMP production was enhanced by glucagon, guanylyl 5'-imidodiphosphate (GMP-PNP), or fluoride, or combinations of these. Adenosine, adenosine monophosphate (AMP) and adenosine diphosphate (ADP) at a concentration of 10(-3) mol/l antagonized the effects of all stimulants. These data suggest that inhibitory effects are exercised at the catalytic moiety of the adenylate cyclase system, or at the transducer function between hormone receptor and catalytic unit. In contrast, adenosine at a concentration of 10(-5) mol/l antagonized glucagon- but not fluoride-stimulated adenylate cyclase activity.
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PMID:Adenylate cyclase activity in human liver membranes and its inhibition by adenosine and adenine nucleotides. 21 Apr 96

The effect of adenosine in insulin secretion and adenylate cyclase activity of rat islets of Langerhans was investigated. Adenosine inhibited insulin secretion stimulated by glucose, glucagon, prostaglandin E2, tolbutamine and theophylline. Adenosine decreased basal adenylate cyclase activity of the islets as well as that stimulated by glucagon prostaglandin E2 and GTP, although fluoride-stimulated activity was not affected. Neither insulin secretion nor adenylate cyclase activity of the islets was affected by adenine, AMP or ADP. The inhibitory effect of adenosine on adenylate cyclase activity was not altered by either phenoxybenzamine (alpha-adrenergic blocker) or propranolol (beta-adrenergic blocker), suggesting that the effect is not mediated through the adrenergic receptors of the islet cells. These results suggest that the intracellular concentration of adenosine in the beta-cell may play a role in regulating insulin secretion and that this effect may be mediated via alterations in the activity of adenylate cyclase in the beta-cell.
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PMID:Adenosine and the regulation of insulin secretion by isolated rat islets of Langerhans. 32 13

Rat liver plasma membranes are shown to catalyze the formation of adenosine 5'-phosphoroglycerol and adenosine 5'-phosphoromethanol from ATP and glycerol or methanol, respectively. In the presence of 2.7 M glycerol and 1 mM ATP, 30 nmol of adenosine 5'-phosphoroglycerol were formed in 10 min per mg of rat liver plasma membranes. The structures of these phosphodiesters were determined from the following evidence. Radioactivity was incorporated into the nucleotide from [alpha-32P]ATP, [2,8-3H]ATP, or [2-3H]glycerol. Treatment with snake venom phosphodiesterase I converted the nucleotides to AMP. The compound formed from glycerol and ATP co-migrated with adenosine 5'-phosphoroglycerol synthesized from glycerol and adenosine 5'-phosphoromorpholidate in five thin layer chromatography systems. The methyl derivative co-migrated with adenosine 5'-phosphoromethanol synthesized from methanol and adenosine 5'-phosphormorpholidate in several thin layer chromatography systems. The synthesis of these phosphodiesters was also catalyzed by chicken embryo fibroblast membranes and solubilized rat liver plasma membranes but not by rat heart plasma membrane preparations. Formation of significant amounts of these phosphodiesters required relatively high concentrations of the alcohols (greater than 1 M). The alcohol concentration dependence did not exhibit substrate saturation at physiologically meaningful concentrations of glycerol or methacol. It is proposed that either the alcohols examined were not the natural substrates for this enzyme or that the alcohol/AMP phosphodiesters were formed as a result of trapping of an enzyme/nucleotide intermediate. Adenosine 5'-phosphoroglycerol formation was inhibited approximately 50% by 15 mM NaF. Epinephrine, norepinephrine, glucagon, and prostaglandin E1 were without effect. Alloxan, an inhibitor of adenylate cyclase did not inhibit formation of adenosine 5'-phosphoroglycerol. It is concluded that adenylate cyclase was not responsible for formation of these phosphodiesters. The physiological significance of this reaction remains undefined.
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PMID:Formation of adenosine 5'-phosphoroglycerol from ATP and glycerol by rat liver plasma membranes. 83 37

Adenosine inhibits the rat liver adenylate cyclase system at a regulatory site that is distinct from the glucagon receptor, the guanine nucleotide regulatory site, and the active site involved in catalysis of ATP to cyclic AMP. The effects of the nucleoside are also independent of the concentration of uncomplexed ATP (ATP4-) in the assay medium. Glucagon, but not guanine nucleotides, sensitizes the system to inhibition by adenosine. Depending on assay conditions, the hormone can shift the concentration of adenosine required for 50% inhibition by as much as 10-fold. Under optimal conditions, the apparent Ki for adenosine is 25 micron. Both Mg2+ and Mn2+ increase adenylate cyclase activity and, in order of relative potency, increase the sensitivity of the enzyme to adenosine inhibition; Mn2+ is 50- to 100-fold more potent than Mg2+. The adenosine inhibitory site exhibits stringent structural requirements for nucleoside action. Most alterations of the purine ring result in loss of activity, whereas alterations in the ribose ring are tolerated, and some deoxyadenosine analogs are even more effective than adenosine. Naturally occurring nucleosides and nucleotides, such as inosine, guanosine, and 5'-AMP, are inactive. Analog studies reveal also that inhibition of the hepatic system occurs at a site which is clearly different from the sites through which adenosine activates other adenylate cyclase systems, and that the liver enzyme appears to have no site for activation by the nucleoside.
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PMID:Regulation by glucagon and divalent cations of inhibition of hepatic adenylate cyclase by adenosine. 89 90

The effects of various nucleosides and nucleotides upon glucagon secretion from the isolated perfused rat pancreas were studied. Increasing glucagon secretion was found with increasing concentrations of exogenous cyclic AMP (2 X 10(-4) M, 2 X 10(-3) M and 1 X 10(-2) M). Stimulation of alpha cell secretion was also found with 2 X 10(-3) M 2'AMP, 3'AMP, 5'AMP, ADP, Adenosine, NADP, and NADPH. One X 10(-3) M cyclic GMP elicited significant glucagon secretion. The pattern of glucagon release was similar in all cases with peak secretion occurring during the 30- to 90-s time period following initiation of the stimulus. No significant increase of glucagon secretion was found in response to ATP, guanosine, 2'GMP, 3'GMP, 5'GMP, GTP, xanthosine, inosine, adenine, xanthine, thymidine, cytidine, ribose, nicotinamide, and uric acid. On the basis of the above results, the structural requirement for stimulation of glucagon secretion appears to be adenine linked to ribose, with phosphate groups being unnecessary. The conclusion of this study is that a new class of compounds capable of stimulating glucagon secretion has been identified, and important questions are thus raised about the mechanism of the action of exogenous cyclic AMP.
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PMID:Nucleotide and nucleoside stimulation of glucagon secretion. 110 53

The role of cyclic-adenosine monophosphate (cAMP) and calcium (Ca2+) in the metabolic responses to adenosine was studied in isolated hepatocytes from fed rats. In the presence of 1.2 mM Ca but not in the absence of Ca2+, adenosine stimulated ureagenesis without increasing cAMP. Adenosine inhibited the glucagon mediated increase in cAMP. Adenosine increased free cytoplasmic Ca2+ provided that cells were incubated in the presence of external Ca2+. In the absence of added Ca2+ adenosine did not stimulate ureagenesis or the movements of Ca2+. It is suggested that, in the liver cell, Ca2+ may be a second messenger for adenosine.
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PMID:Metabolic responses of isolated hepatocytes to adenosine; dependence on external calcium. 165 Apr 15

The effect of hormones on cell volume was studied in isolated perfused rat liver by assessing the intracellular water space as the difference between a [3H]inulin- and a [14C]urea-accessible space. The intracellular water space (control value 559 +/- 7 microliters/g of liver; n = 88) increased on addition of insulin (35 nM) or phenylephrine (5 microM) by 12 or 8% respectively, whereas it decreased with cyclic AMP (cAMP; 50 microM), glucagon (100 nM) or adenosine (50 microM) by 9, 13 or 6% respectively. Both insulin and glucagon exerted half-maximal effects on cell volume and cellular K+ balance at hormone concentrations found physiologically in the portal vein. Adenosine-induced cell shrinkage was explained by a net K+ release from the liver. Phenylephrine (5 microM) led to cell swelling by about 8%, which was additive to insulin-induced swelling. Extracellular ATP (20 microM) induced cell shrinkage by about 6%; this was additive to adenosine-induced shrinkage. Vasopressin (15 nM) did not appreciably change cell volume, but induced marked cell shrinkage when glucagon or cAMP was present. Insulin- and phenylephrine-induced cell swelling was counteracted by cAMP. Hormone-induced changes of intracellular water space could sufficiently explain accompanying liver mass changes induced by glucagon, cAMP, adenosine or vasopressin, but not those by phenylephrine and extracellular ATP. The data show that liver cell volume is subject to hormonal regulation, in part owing to modification of cellular K+ balance. Glucagon- and insulin-induced cell volume changes occur already in the presence of physiological hormone concentrations. The effects of Ca2(+)-mobilizing hormones on cell volume are not uniform. In view of the recently established role of cell volume changes in modulating liver cell function, the present findings open a new perspective on the mechanisms of hormone action in liver, underlining our previous hypothesis that cell volume changes may represent a 'second messenger' of hormone action.
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PMID:Regulation of cell volume in the perfused rat liver by hormones. 166 Feb 61

The effects of an adenosine analog, N6-phenyl-isopropyl-adenosine (PIA), on the glucagon-stimulated adenylate cyclase activity in rat hepatic membranes were studied. Adenosine at high concentrations (greater than 10 microM) has been reported exclusively to inhibit the adenylate cyclase via intracellular P-sites of the hepatic membrane. The stimulation by glucagon of the enzyme was attenuated by nanomolar concentrations of PIA in the presence of low concentrations (less than 1.0 microM) of GTP, indicating the effect of the guanine nucleotide inhibitory system (Ni). This inhibition by PIA required the presence of sodium chloride and was antagonized with isobutyl methylxanthine, an antagonist for the extracellular R-site receptors. The inhibitory effects of PIA disappeared and reversed into a stimulatory phase with increasing concentrations of GTP, suggesting the presence of a stimulatory (Ns) and an inhibitory (Ni) guanine nucleotide system of the enzyme in the action of the adenosine. PIA concentrations over a micromolar were observed to stimulate the enzyme activity in a GTP-dependent manner, indicating the presence of the stimulatory receptor (A2 or Ra) coupled to the Ns. These results suggest that receptors for adenosine of the inhibitory type (A1 or Ri) and the stimulatory type (A2 or Ra) are present on the rat hepatic membrane, showing multiple controls of the adenylate cyclase system, depending on the cellular concentrations of GTP and/or sodium chloride.
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PMID:Multiple controls by adenosine receptors on the adenylate cyclase in the rat hepatic membrane. 169 17


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