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)

In glycogen particle suspensions prepared from fed rats given either glucagon or glucose in order to increase or decrease the phosphorylase a concentration, respectively, glucose stimulation of synthase phosphatase activity was observed. In preparations from glucagon-treated rats, addition of glucose stimulated synthase and phosphorylase phosphatase simultaneously and not sequentially. Synthase phosphatase stimulation was glucose concentration dependent even when phosphorylase a had been rapidly reduced to a low level. The estimated A0.5 for glucose stimulation of synthase phosphatase activity was 27 mM. An A0.5 for glucose stimulation of phosphorylase phosphatase activity could not be estimated since activity was still increasing with concentrations of glucose as high as 200 mM. In preparations from glucose-treated rats which contain virtually no phosphorylase a, glucose stimulation was still apparent but the A0.5 was increased modestly (36 mM). Stimulation of synthase phosphatase activity was specific for glucose. Several other monosaccharides and the polyhydric alcohol sorbitol were ineffective.
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PMID:Direct glucose stimulation of glycogen synthase phosphatase activity in a liver glycogen particle preparation. 632 Jul 43

In this report we describe a novel in vitro phenomenon involving the interaction of insulin with purified protein phosphatases. Evidence is presented that porcine insulin is capable of activating and binding to rabbit skeletal muscle protein phosphatases in vitro. Its effects were examined on four rabbit skeletal muscle protein phosphatases. Two of these, phosphatases C-I and C-II, are of Mr approximately 35,000 and are the dissociated forms of protein phosphatase. The two other phosphatases, H-I and H-II, have Mr approximately 250,000 by gel filtration and represent nondissociated forms of phosphatase. Insulin reproducibly activated homogeneous preparations of protein phosphatase C-II and H-II approximately 3-5-fold in vitro. The activation was dependent on temperature, time, and insulin concentration. The activities of the phosphatases toward both phosphorylase alpha and histone were affected, indicating that this was not a substrate-directed effect. The activation phenomenon was not mimicked by insulin A or B chains, somatostatin, glucagon, or bovine serum albumin, and could be prevented by insulin antiserum. 125I-Insulin was shown to bind to the protein phosphatases by solid phase binding assays. Phosphatases C-I, C-II, and H-II, but not phosphatase H-I, were found to bind insulin reversibly. Half-maximal binding to the protein phosphatases was observed at approximately 5 X 10(-10) M insulin. Labeled insulin was found to coelute with protein phosphatase H-II on gel filtration when a mixture of the two was chromatographed, providing evidence for the formation of an enzyme-insulin complex. These findings suggest that certain protein phosphatases may have a specific binding site(s) for insulin and that these insulin-phosphatase complexes may also exhibit enhanced catalytic activity.
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PMID:A novel in vitro interaction of insulin with rabbit skeletal muscle protein phosphatases. 632 53

A 59-year-old Japanese farmer with asymptomatic fasting hypoglycemia and with exaggerated hypoglycemic episodes induced by insulin and oral hypoglycemic agent administered for his postprandial hyperglycemia was diagnosed as glycogen storage disease type I. This diagnosis was suggested by unresponsiveness of blood glucose level to glucagon and confirmed by 13% normal level of glucose 6-phosphatase activity in liver biopsy specimen and by the presence of PAS positive amylase digestable glycogen in liver specimen. This case was associated with an incomplete type of Fanconi syndrome characterized by hyperphosphaturic hypophosphatemia, partial aminoaciduria, mild proteinuria and hyperuricosuric normouricemia in spite of the lactic acidemia due to glycogen storage disease type I. The etiology for the absence of hypoglycemia and other typical manifestations of glycogen storage disease type I was studied. The glucose production from glycogen by lysosomal alpha 1,4-glucosidase especially at prolonged fasting and the presence of postprandial hyperglycemia by insulin deficiency are regarded as responsible for keeping this patient free from typical manifestations of glycogen storage disease type I.
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PMID:A case of glycogen storage disease type I associated with an incomplete type of Fanconi syndrome; the protective role of lysosomal alpha 1,4-glucosidase and insulin deficiency against hypoglycemia. 639 62

Three stages of development of hepatic glycogen metabolism in the rat were studied. These included the last stage of gestation, in which large scale synthesis and accumulation of glycogen takes place, the perinatal period of glycogenolysis, and the suckling period up to and including weaning. The role of insulin in the regulation of the key rate-limiting enzymes of glycogen synthesis (glycogen synthase) and glycogen breakdown (glycogen phosphorylase) was studied as was the role of the key phosphoprotein phosphatase enzymes that regulate activation of synthase (synthase phosphatase) and inactivation of phosphorylase (phosphorylase phosphatase). Glycogen accumulates in significant quantities on days 20-21 of gestation in the rat (term, 22 days). Associated with this increased rate and amount of glycogen accumulation is an increase in glycogen synthase a and synthase phosphatase and phosphorylase phosphatase activities associated with the endoplasmic reticulum (ER). Concomitantly, fetal insulin levels are elevated as is the insulin to glucagon molar ratio and the synthase a/phosphorylase a ratio. At birth, these hepatic glycogen stores are rapidly degraded, and synthase a levels are diminished, as are ER-associated synthase phosphatase and phosphorylase phosphatase activities. Phosphorylase a levels are markedly elevated at this time as well. Insulin levels are decreased, as is the insulin to glucagon molar ratio. Gradually over a period of 4 weeks after birth, glycogen levels increase in the liver, accompanied by increased ER-associated phosphatase activities and an increased insulin to glucagon molar ratio. The data support a role for increased ambient insulin concentrations in regulation of the periods of active glycogen synthesis and accumulation in pre- and postnatal rat liver. A possible site of action of insulin is the ER and associated phosphoprotein phosphatase activities.
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PMID:Regulation of hepatic glycogen metabolism in pre- and postnatal rats. 640 92

Isolated rat hepatocytes were incubated in a medium containing 0.1 mM [32P]phosphate (0.1 mCi/ml) before exposure to epinephrine, glucagon or vasopressin. 32P-labeled glycogen synthase was purified from extracts of control or hormone-treated cells by the use of specific antibodies raised to rabbit skeletal muscle glycogen synthase. Analysis of the immunoprecipitates by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate indicated that a single 32P-labeled polypeptide, apparent Mr 88000, was removed specifically by the antibodies and corresponded to glycogen synthase. Similar electrophoretic analysis of CNBr fragments prepared from the immunoprecipitate revealed that 32P was distributed between two fragments, of apparent Mr 14000 (CB-1) and 28000 (CB-2). Epinephrine, vasopressin or glucagon increased the 32P content of the glycogen synthase subunit. CB-2 phosphorylation was increased by all three hormones while CB-1 was most affected by epinephrine and vasopressin. These effects correlated with a decrease in glycogen synthase activity. From studies using rat liver glycogen synthase, purified by conventional methods and phosphorylated in vitro by individual protein kinases, it was found that electrophoretically similar CNBr fragments could be obtained. However, neither cyclic-AMP-dependent protein kinase nor three different Ca2+-dependent enzymes (phosphorylase kinase, calmodulin-dependent protein kinase, and protein kinase C) were effective in phosphorylating CB-2. The protein kinases most effective towards CB-2 were the Ca2+ and cyclic-nucleotide-independent enzymes casein kinase II (PC0.7) and FA/GSK-3. The results demonstrate that rat liver glycogen synthase undergoes multiple phosphorylation in whole cells and that stimulation of cells by glycogenolytic hormones can modify the phosphorylation of at least two distinct sites in the enzyme. The specificity of the hormones, however, cannot be explained simply by the direct action of any known protein kinase dependent on cyclic nucleotide or Ca2+. Therefore, either control of other protein kinases, such as FA/GSK-3, is involved or phosphatase activity is regulated, or both.
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PMID:Control of glycogen synthase phosphorylation in isolated rat hepatocytes by epinephrine, vasopressin and glucagon. 643 31

The effects of vasoactive intestinal polypeptide (VIP) on several enzymes of glycogen metabolism in rat hepatocytes were compared with those of glucagon and of vasopressin (ADH). VIP caused phosphorylase activation and glycogenolysis in hepatocytes from fed rats. In hepatocytes from fasted rats incubated with glucose, lactate, and pyruvate, VIP inhibited net glycogen deposition, inactivated glycogen synthase, and activated phosphorylase. VIP was about 100-fold less potent than glucagon and 1,000-fold less potent than ADH in causing activation of phosphorylase. The ability of VIP to activate phosphorylase was not altered by chelation of the calcium in the medium. The half maximal effective doses of VIP for both phosphorylase activation and stimulation of glycogenolysis were 10-30 nM. Treatment with VIP, ADH, or glucagon did not decrease phosphorylase phosphatase activity. Each of these hormones, however, lengthened the lag time before synthase phosphatase activity was expressed in vitro. Other gut hormones tested did not affect hepatocyte glycogen metabolism. These results do not support the concept of physiologic control of hepatic glycogen metabolism by VIP or by other gut hormones.
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PMID:Effect of vasoactive intestinal polypeptide on glycogen metabolism in rat hepatocytes. 680 98

Hydroxymethylglutaryl CoA reductase catalyzes the limiting step in cholesterol synthesis in liver and other tissues. Beginning in 1973 studies with subcellular systems established that microsomal reductase is inactivated with ATP(Mg) and reductase kinase, and restored to full activity with phospho-protein phosphatase. By contrast reductase kinase is inactivated with phosphatase and reactivated with a second protein kinase (reductase kinase kinase). This bicyclic system has now been confirmed in terms of homogeneous enzyme components and by direct reversible phosphorylation with [gamma 32P]ATP in several laboratories. Short-term endocrine control of reductase and reductase kinase has been demonstrated in intact rat hepatocytes. Preincubation of cells with glucagon brought about a fall in the expressed activity of reductase and a rise in reductase kinase consistent with net phosphorylation of both enzymes. Total reductase levels were also severely depressed after glucagon. Addition of insulin to suspensions of hepatocytes had the reverse effect on expressed activity of reductase (elevated) and reductase kinase (depressed). Insulin also prevented the decay in total reductase activity. Since both protein kinases identified in this system are cAMP-insensitive, it was possible that hormonal signaling is mediated through the protein phosphatase that acts on both reductase kinase and reductase. In recent studies we have shown that the rate of activation of endogenous reductase in hepatocyte extracts (microsomes plus cytosol) is responsive to hormonal modulation. Pretreatment of hepatocytes with insulin increases apparent reductase phosphatase activity in extracts while glucagon diminishes the rate of reductase activation. HMG CoA is converted to mevalonate by the reductase enzyme. In hepatocytes mevalonate is rapidly converted to cholesterol and to a variety of isoprene derivatives. Expressed reductase activity falls precipitously when hepatocytes are incubated with mevalonate (added in the form of mevalono-lactone). As in the case with glucagon pretreatment reductase phosphatase is rapidly diminished. (Mevalonate itself is not inhibitory to reductase or reductase phosphatase activity in subcellular systems.) It is probable that a product of mevalonate metabolism generated in intact cells may act as a reductase phosphatase inhibitor. Among these added inorganic pyrophosphate inhibited reductase phosphatase at low concentrations.
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PMID:Short-term regulation of hydroxymethylglutaryl coenzyme A reductase by reversible phosphorylation: modulation of reductase phosphatase in rat hepatocytes. 705 70

Immunotitrations of rat liver hydroxymethylglutaryl-CoA (HOMeGlt-CoA) reductase activity were performed before and after short-term changes in the nutritional or hormonal state of the animals. Changes in enzyme activity (increase or decrease) within 1 h following cholesterol feeding or glucagon or mevalonolactone administration to normal rats, or insulin administration to diabetic rats were accompanied by no change in the specific activity of the enzyme, as determined from the quantity of enzyme activity inactivated by a fixed quantity of antibody. These results support the conclusion that the loss in enzyme activity was due to conversion of the enzyme to immuno-unreactive products. In agreement with this conclusion the enzyme activity lost after these short-term physiological changes was not restorable by phosphoprotein phosphatase action. On the other hand, incubation of rat liver microsomes with ATP and Mg2+ decreased the specific activity of HOMeGlt-CoA reductase about tenfold, as determined by immunotitration. The low specific activity produced under these conditions was increased by phosphatase action to nearly the original level. The above evidence suggests that the changes in HOMeGlt-CoA reductase activity that resulted from short-term physiological changes in hormonal or nutritional states of an animal were brought about by a change in the quantity of enzyme, and not by reversible phosphorylation of pre-existing enzyme.
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PMID:Regulation of short-term changes in hepatic beta-hydroxy-beta-methylglutaryl-CoA reductase activity. 711 48

Protein kinase activity in incubated liver slices from 35 degrees C heat-acclimated (HA) hamsters was 70% higher than in similar slices from 23 degrees C control (C) hamsters. Adding glucagon to the incubation medium increased protein kinase activity by 65% in slices from C animals, but by only 30% in slices from HA animals. Binding of [3H]cAMP to proteins of a low-speed supernatant fraction of incubated and homogenized slices was 30% lower for HA than for C hamsters. For each acclimation group this binding was reduced 30% by incubation of the slices with glucagon. The activities of phosphorylase kinase, phosphorylase phosphatase, and phosphorylase alpha in slices incubated with or without glucagon did not differ between groups. Addition of glucagon increased phosphorylase kinase by 30% and phosphorylase alpha by 40% but caused no change in phosphorylase phosphatase activity. These results suggest that heat acclimation of the hamster increases the amount of a species of liver protein kinase that is different from the one that mediates the effect of glucagon on glycogenolysis.
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PMID:Protein kinase activity in liver of heat-acclimated hamsters. 712 94

Cyclosporin A and the macrolide tacrolimus (FK506) are powerful immunosuppressive drugs that in T cells inhibit the calcium/calmodulin-dependent phosphatase calcineurin thereby preventing the activation of T-cell-specific transcription factors, such as NF-AT, involved in lymphokine gene expression. While this may explain, at least in part, the mechanism of cyclosporin A/FK506 immunosuppression, additional mechanisms have to be invoked in order to explain the pharmacological properties and toxic effects of these drugs, such as nephrotoxicity and neurotoxicity. We have studied the effects of cyclosporin A and FK506 on calcineurin phosphatase activity and gene transcription mediated by the cAMP-responsive element (CRE), a binding site of the ubiquitous transcription factor CREB. A reporter gene was placed under the transcriptional control of the CRE of the rat glucagon gene and transiently transfected into the glucagon-expressing cell line alpha TC2. Cyclosporin A and FK506 inhibited depolarization-induced gene transcription in a concentration-dependent manner (IC50 of about 1 nM and 30 nM for FK506 and cyclosporin A, respectively). Both cyclosporin A and FK506 inhibited calcineurin phosphatase activity at drug concentrations that inhibited gene transcription. The FK506 analogue rapamycin had no effect on calcineurin activity and gene transcription, but excess concentrations of rapamycin prevented the effects of FK506 on both calcineurin activity and gene transcription. These results support the notion that the interaction of drug-immunophilin complexes with calcineurin may be the molecular basis of cyclosporin A/FK506-induced inhibition of CREB/CRE-mediated gene transcription. The ability to interfere with CREB/CRE-mediated gene transcription represents a novel mechanism of cyclosporin A/FK506 action which may underlie pharmacological effects and toxic manifestations of these potent immunuosuppressive drugs.
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PMID:The immunosuppressive drugs cyclosporin A and FK506 inhibit calcineurin phosphatase activity and gene transcription mediated through the cAMP-responsive element in a nonimmune cell line. 750 60


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