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)

Endosomes have recently been identified as one major site of glucagon degradation in intact rat liver. In this study, a cell-free system has been used to assess the role of ATP-dependent acidification in endosomal glucagon degradation and identify the glucagon products generated. Percoll gradient fractionation of Golgi-endosomal fractions prepared 10-30 min after injection of [125I]iodoglucagon showed a time-dependent shift of the radioactivity towards high densities. Regardless of time, the radioactivity was less precipitable by trichloroacetic acid (Cl3Ac) at high densities than at low densities. Chloroquine treatment slightly increased the density shift of the radioactivity and decreased its Cl3Ac-precipitability throughout the gradient. Incubation of endosomal fractions containing [125I]iodoglucagon in 0.15 M-KCl at 30 degrees C resulted in a time- and pH-dependent generation of Cl3Ac-soluble radioactivity, with a maximum at pH 4 (t1/2, 7 min). At pH 5, 1,10-phenanthroline, bacitracin and p-chloromercuribenzoic acid partially inhibited [125I]iodoglucagon degradation. At pH 6-7, ATP stimulated [125I]iodoglucagon degradation by 5-10-fold and caused endosomal acidification as judged from Acridine Orange uptake. The effects of ATP were inhibited by chloroquine, monensin, N-ethylmaleimide and dansylcadaverine. Poly(ethylene glycol) (PEG) precipitation of the radioactivity associated with endosomes showed that lowering the pH below 5.5 caused dissociation of the glucagon-receptor complex, and that, regardless of incubation conditions, all degraded [125I]iodoglucagon diffused extraluminally. On h.p.l.c., at least three products less hydrophobic than [125I]iodoglucagon were identified in incubation mixtures along with monoiodotyrosine. Radiosequence analysis of the products revealed one major cleavage located C-terminally to Tyr-13 and two minor cleavages affecting Thr-5-Phe-6 and Phe-6-Thr-7 bonds. It is concluded that glucagon degradation in liver endosomes is functionally linked to ATP-dependent endosomal acidification and involves several cleavages in the glucagon sequence.
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PMID:Degradation of glucagon in isolated liver endosomes. ATP-dependence and partial characterization of degradation products. 174 49

The interrelationship between glycogen biosynthesis and do novo glucose formation in rats was studied by determining the oxaloacetic acid, ATP, and glycogen levels in the tissues of healthy starved rats and during the growth of transplantable hepatomas with different rates of growth. From the results obtained it was proposed that glycogen biosynthesis and de novo glucose formation are mutually enhanced and coupled processes. The validity of this conclusion was confirmed by in vitro model experiments involving the use of isolated-liver perfusion. Results of a multiple regression analysis indicated that the efficiency of gluconeogenesis and glycogen deposition is determined by the supply of oxygen to the liver, by the oxaloacetic acid content of this organ, and also by the degree of reduction of the glucose precursor. It was also shown that the ability of glucocorticoids and glucagon to enhance gluconeogenesis is dependent on the supply of oxygen to the liver. From the results of this in vivo and in vitro comparative study it is concluded that deposition of glycogen in the liver and possibly also in the brain is determined by the efficiency of gluconeogenesis.
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PMID:Intracellular factors determining the deposition of glycogen. The role of gluconeogenesis. 175 56

We recently reported that the secretion of insulin and glucagon by isolated murine islets is pulsatile and suggested that the pacemaker controlling these hormone oscillations is present in the islet. In the present study, we tested the hypothesis of an intrinsic islet neural controlling mechanism for the observed hormone pulsatility. Nerve blockade was attempted by infusion of tetrodotoxin (TTX) on a background of combined adrenergic and cholinergic blockade with atropine, propranolol, and phentolamine, (ATX). Because TTX acts by blocking Na+ channels, we also studied the effects of other cationic channel manipulations on the amplitude and frequency of the oscillations. The normal frequency and amplitude of glucagon and insulin oscillations were not affected by ATX. In contrast, TTX infusion increased the amplitude of insulin (198.6 +/- 20.9 vs. 507.2 +/- 62.8 pg/min, p less than 0.05, n = 4) and shortened the period from 5.03 +/- 0.26 to 3.33 +/- 0.0 min without affecting glucagon cycles. Whereas the Ca2+ ionophore A23187 had no effect on either hormone oscillation, the ATP-sensitive K+ channel blocker glyburide only increased the amplitude of insulin and decreased the amplitude of glucagon, without altering the frequencies. These data suggest that an intrinsic autonomously functioning islet nervous system is the pacemaker for the insulin oscillations and that the control of glucagon cycles differs from that of insulin.
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PMID:Effect of nerve blockade on pulsatile insulin and glucagon secretion in vitro. 178 Mar 25

The effect of glucose hyperalimentation on energy metabolism in the cirrhotic rat liver after 70% hepatectomy was studied. After resection, rats received either 30 kcal/kg per day (group I) or 200 kcal/kg per day (group II) of glucose for 48 h. In both groups, hepatic mitochondrial ATP synthesis was accelerated when palmitic acid was used as substrate and suppressed when pyruvate was used. This suggests that the energy substrate of the remnant liver was principally fatty acids rather than glucose. Hepatic energy charge was within normal limits in group I, but decreased significantly in group II after hepatectomy. An abundance of glucose in the early postoperative period, therefore, caused a hepatic energy derangement by suppressing fatty acids utilization; this suppression was corroborated by the findings of lower immunoreactive glucagon and non-esterified fatty-acid concentrations in group II. To determine optimal glucose administration, the predicted value of glucose disposal rate (GDR) was calculated after an intravenous glucose tolerance test. GDR decreased significantly after hepatectomy and did not increase appreciably even with a large dose of insulin administration. These results suggest that glucose administration should be tailored to the GDR values after resection of the cirrhotic liver.
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PMID:Glucose overload and hepatic energy metabolism after resection of the cirrhotic liver in rats. 178 71

1. In several tissues, 2-methylthio adenosine triphosphate (2MeSATP) is a very potent P2y-purine agonist. In rat hepatocytes, 2MeSATP half-maximally activated glycogen phosphorylase at 20 nM and was therefore about 25 times more effective than ATP (Ka 0.5-0.8 microM). This strong glycogenolytic potency of 2MeSATP suggests on its own the presence of P2Y-purinoceptors in liver. 2. Displacement of the radioligand ATP alpha[35S] from its receptor however occurred at much higher concentrations of 2MeSATP than was anticipated on the basis of its glycogenolytic potency. 3. The interaction of 2MeSATP with the receptor, characterized with ATP alpha[35S] as radioligand, cannot be considered as a pure competitive interaction. 4. 2MeSATP did not share the ability of ATP to counteract the effect of glucagon on the adenosine 3':5'-cyclic monophosphate levels. 5. 2MeSATP barely increased the levels of inositol trisphosphate (IP3). 6. The glycogenolytic effect of 2MeSATP was completely abolished by pretreatment of the hepatocytes with phorbol myristic acetate. 7. It is tentatively concluded that 2MeSATP and ATP are interacting with different P2 purinoceptors.
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PMID:Characterization of the biological effects of 2-methylthio-ATP on rat hepatocytes: clear-cut differences with ATP. 179 99

Haemoglobin damaged by exposure of red blood cells to oxidants is rapidly degraded by a proteolytic pathway which does not require ATP [Fagan, Waxman & Goldberg (1986) J. Biol. Chem. 261, 5705-5713]. By fractionating erythrocyte lysates, we have purified two proteases which hydrolyse oxidatively damaged haemoglobin (Ox-Hb). One protease hydrolysed small fluorogenic substrates in addition to Ox-Hb. Its molecular mass was approximately 700 kDa and it consisted of several subunits ranging in size from 22 to 30 kDa. This enzyme may be related to the high-molecular-mass multicatalytic proteinase previously isolated from a variety of tissue and cell types. The other Ox-Hb-degrading activity had an apparent molecular mass of 400 kDa on gel filtration, a subunit size of 110 kDa and an isoelectric point between 4.5 and 5.0. This protease also hydrolysed the small polypeptides insulin and glucagon, as well as other large proteins such as lysozyme. Insulin blocked the degradation of Ox-Hb and Ox-Hb blocked the hydrolysis of insulin by the purified protease. Thiol reagents and metal chelators strongly inhibited the hydrolysis of both Ox-Hb and insulin, whereas inhibitors of serine, aspartic and thiol proteases had little effect. These properties suggest that the Ox-Hb-degrading activity purified from rabbit erythrocytes is the cytosolic insulin-degrading enzyme that is believed to play a role in the metabolism of insulin in several tissues. We propose that this enzyme may also function as a key component in a cytoplasmic degradative pathway responsible for removing proteins damaged by oxidants.
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PMID:Purification of a protease in red blood cells that degrades oxidatively damaged haemoglobin. 187 13

Adenylate cyclase activity in isolated rat liver plasma membranes was inhibited by NADH in a concentration-dependent manner. Half-maximal inhibition of adenylate cyclase was observed at 120 microM concentration of NADH. The effect of NADH was specific since adenylate cyclase activity was not altered by NAD+, NADP+, NADPH, and nicotinic acid. The ability of NADH to inhibit adenylate cyclase was not altered when the enzyme was stimulated by activating the cyclase was not altered when the enzyme was stimulated by activating the Gs regulatory element with either glucagon or cholera toxin. Similarly, inhibition of Gi function by pertussis toxin treatment of membranes did not attenuate the ability of NADH to inhibit adenylate cyclase activity. Inhibition of adenylate cyclase activity to the same extent in the presence and absence of the Gpp (NH) p suggested that NADH directly affects the catalytic subunit. This notion was confirmed by the finding that NADH also inhibited solubilized adenylate cyclase in the absence of Gpp (NH)p. Kinetic analysis of the NADH-mediated inhibition suggested that NADH competes with ATP to inhibit adenylate cyclase; in the presence of NADH (1 mM) the Km for ATP was increased from 0.24 +/- 0.02 mM to 0.44 +/- 0.08 mM with no change in Vmax. This observation and the inability of high NADH concentrations to completely inhibit the enzyme suggest that NADH interacts at a site(s) on the enzyme to increase the Km for ATP by 2-fold and this inhibitory effect is overcome at high ATP concentrations.
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PMID:Inhibition of hepatic adenylate cyclase by NADH. 187

Isoproterenol, epinephrine, phenylephrine and glucagon inhibited proteolysis in isolated perfused rat hearts. All of these agents had a positive inotropic effect, while isoproterenol and glucagon were shown to increase cyclic AMP content. The catecholamines, but not glucagon, partially depleted the adenine nucleotide pool, but the creatine-phosphate/creatine ratio was unchanged or increased. Isoproterenol markedly increased lactate production and caused release of lactate dehydrogenase. The effects of isoproterenol on these parameters, including proteolysis, were blocked by propranolol and verapamil. Isoproterenol also inhibited proteolysis when perfusate calcium was reduced from 2.5 to 0.5 mM; but, in this circumstance, isoproterenol did not deplete ATP. In hearts arrested with tetrodotoxin, neither isoproterenol nor glucagon inhibited proteolysis and neither of them depleted ATP. Both hormones still increased cyclic AMP content. These findings suggest that cyclic AMP may not be involved in the control of proteolysis, and that the effects of isoproterenol and glucagon are mediated via effects on contractility. The studies stress the importance of preventing adenine nucleotide depletion and controlling contractility in experiments on the mechanisms of inotropic agents on cardiac protein turnover.
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PMID:Catecholamines, glucagon, energy metabolism and protein degradation in rat heart. 196 72

The effects of ATP and ADP structural analogues (2-methylthio ATP; alpha,beta-methylene ADP) on somatostatin secretion were tested in dogs. Insulin and glucagon secretion was also evaluated. Our experiments were performed in vivo and in vitro. In vivo, 2-methylthio ATP was infused directly into the pancreaticoduodenal artery of anesthetized dogs and blood was sampled from the pancreaticoduodenal vein. This ATP analogue (approximately 15 microM) immediately induced stimulation of both somatostatin and insulin secretion, which was accompanied by a slight reduction of glycemia. A delayed increase in glucagon output was observed. In vitro, using the isolated perfused dog pancreas uncinate process, alpha,beta-methylene ADP, a stable ADP analogue (16.5 microM), was infused in the presence of a substimulating glucose concentration (4.2 mM). Under these conditions, alpha,beta-methylene ADP immediately induced the stimulation of somatostatin secretion without affecting basal insulin and glucagon secretion. In conclusion our results suggest the presence of P2 purinoceptors on pancreatic somatostatin secreting cells.
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PMID:P2 purinoceptor agonists stimulate somatostatin secretion from dog pancreas. 197 83

Autophagy is the major process by which cells degrade their own cytoplasm. Autophagy begins with the sequestration of a portion of the cytoplasm by a membraneous organelle called a phagophore. The resulting vacuole (autophagosome) can fuse with an endocytic vacuole to form am amphisome, which subsequently fuses with a lysosome to have its mixed autophagic/endocytic content degraded by lysosomal enzymes. Autophagy is a non-selective bulk process as indicated by the fact that hepatocytic cytosol enzymes with widely different half-lives are sequestered at the same rate. Regulation of autophagy is exerted at the sequestration step by amino acids, purines, ATP-depleting metabolites, cyclic nucleotides, phosphorylation, and hormones like insulin, glucagon and alpha-adrenergic agonists.
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PMID:Non-selective autophagy. 210 95


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