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)

A high affinity Ca2+-stimulated, Mg2+-dependent ATPase (Ca2+-Mg2+-ATPase) was identified in microsomes and plasma membrane vesicles isolated from rat hepatocytes. The distribution of this enzyme was similar to that of the plasma membrane marker enzymes alkaline phosphodiesterase and 5'-nucleotidase. The Ca2+-Mg2+-ATPase had an apparent half-saturation constant of approximately 75 nM for Ca2+. After incubation of rat hepatocytes with 25 nM vasopressin for 3 min, the activity of Ca2+-Mg2+-ATPase was decreased 15-30%. The effect of vasopressin on the activity of this enzyme was near maximal after incubating hepatocytes with vasopressin for only 15 sec. The concentration of vasopressin needed for half-maximal inhibition of this enzyme in hepatocytes was approximately 6 nM. Treatment of the hepatocytes with 10 microM phenylephrine caused about a 10% decrease in ATPase activity while 10 nM glucagon or 200 microU/ml insulin did not affect the enzyme. These findings suggest that inhibition of the Ca2+-Mg2+-ATPase activity may be part of the mechanism by which vasopressin and alpha-adrenergic agonists elevate cytosolic Ca2+ in hepatocytes.
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PMID:Regulation of Ca2+-Mg2+-ATPase activity in hepatocyte plasma membranes by vasopressin and phenylephrine. 613 76

The ATP-dependent calcium transport in plasma membrane vesicles prepared from rat liver was inhibited by 0.1 to 10 microM glucagon. Inhibition of the high affinity (Ca2+-Mg2+)-ATPase was observed concomitantly. This effect was neither mimicked by cyclic AMP nor by dibutyryl cyclic AMP. A study of the structure-activity relationships of six glucagon derivatives demonstrated the specificity of glucagon action since only one or two analogs markedly altered the (Ca2+-Mg2+)-ATPase activity. The study also demonstrated the total absence of correlation between adenylate cyclase activation and (Ca2+-Mg2+)-ATPase inhibition induced by these glucagon derivatives. The decrease in the maximal velocities induced by glucagon of both calcium transport and (Ca2+-Mg2+)-ATPase activity were related to a reduction in the rate of dephosphorylation of the Ca-dependent phosphorylated intermediate of the enzyme. This phosphorylated intermediate was characterized as a 32P-labeled 110,000-dalton protein which accumulated to 50 to 150% over the basal level in the presence of glucagon. The present results demonstrate a novel aspect of the role of glucagon as a calcium-mobilizing agent.
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PMID:Inhibition by glucagon of the calcium pump in liver plasma membranes. 614 15

A novel adenylate cyclase activity was found in crude homogenates of Neurospora crassa. The adenylate cyclase had substantial activity with ATP-Mg2+ as substrate differing significantly from the strictly ATP-Mn2+-dependent enzyme characterized previously. Additionally, the ATP-Mg2+-dependent activity was stimulated two- to fourfold by GTP or guanyl-5'-yl-imido-diphosphate (Gpp(NH)p). We propose that the ATP-Mg2+-dependent, guanine nucleotide-stimulated activity is due to a labile regulatory component (G component) of the adenylate cyclase which was present in carefully prepared extracts. The adenylate cyclase had a pH optimum of 5.8 and both the catalytic and G component were particulate. The Km for ATP-Mg2+ was 2.2 mM in the presence of 4.5 mM excess Mg2+. Low Mn2+ concentrations had no effect on adenylate cyclase activity whereas high concentrations of Mn2+ or Mg2+ stimulated the enzyme. Maximal Gpp(NH)p stimulation required preincubation of the enzyme in the presence of the guanine nucleotide and the K1/2 for Gpp(NH)p stimulation was 110 nM. Neither fluoride nor any of a variety of glycolytic intermediates or hormones, including glucagon, epinephrine, and dopamine, had an effect on ATP-Mg2+-dependent adenylate cyclase activity. However, the enzymatic activity was stimulated not only by GTP but also by 5'-AMP and was inhibited by NADH.
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PMID:Characterization of an ATP-Mg2+-dependent guanine nucleotide-stimulated adenylate cyclase from Neurospora crassa. 621 25

Addition of glucagon to isolated hepatocytes reduced the activity of 6-phosphofructokinase (ATP:D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) and pyruvate kinase (ATP:pyruvate 2-O-phosphotransferase, EC 2.7.1.40). Phosphorylation contributed to the inhibition of pyruvate kinase, but several lines of evidence indicated that this reaction was not responsible for the inhibition of phosphofructokinase. First, the increase in phosphorylation in intact cells induced by increasing the concentration of glucagon did not correlate well with the decrease in enzyme activity. Second, phosphorylation of phosphofructokinase induced by addition of cyclic AMP and Mg2+-ATP or by addition of Mg2+-ATP and the catalytic subunit of the cyclic AMP-dependent protein kinase to hepatocyte extracts had no effect on enzyme activity. Third, ammonium sulfate precipitation of the enzyme from extracts of cells incubated with glucagon abolished the hormone effect. The effect could be restored, however, by the addition of a phosphofructokinase-free extract from glucagon-treated cells to the ammonium sulfate-treated enzyme from either untreated or glucagon-treated cells. These results suggest that the inhibition of phosphofructokinase by glucagon is due to changes in the level of an allosteric effector(s).
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PMID:Mechanism of action of glucagon on hepatocyte phosphofructokinase activity. 625 41

Incubation of solubilized hormone-activated phosphodiesterase from isolated hepatocytes, under conditions likely to favour a dephosphorylation reaction, did not cause a loss of the hormone activation. If, however, the enzyme was incubated with Mg2+ (10 mM) while still associated with its membrane, and subsequently solubilized, the activity of the hormone-stimulated enzyme declined to the level seen in control cells. Diminution of hepatocyte ATP levels to about 20% of control values, by incubation with fructose, blunted the effect of glucagon and abolished the effect of insulin on phosphodiesterase. More severe ATP depletion caused by dinitrophenol abolished the stimulation of the enzyme by both hormones. These effects were not considered likely to be due to altered hormone-binding and are consistent with the involvement of an energy-dependent step in the hormonal activation of phosphodiesterase.
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PMID:Energy-dependent activation and magnesium--dependent inactivation of hepatocyte hormone-sensitive phosphodiesterase. 626 Feb 24

Isolated rat hepatocytes were used to investigate the possibility of a short-term effect of glucagon on the synthesis of triacylglycerols in the liver. Incubation of hepatocytes in the presence of glucagon, followed by homogenization in a buffer containing F- (50 mM) and EDTA (2.5 mM), resulted in a 53% decrease in activity of microsomal diacylglycerol acyltransferase (EC 2.3.1.20), the only enzyme that is exclusively involved in the synthesis of triacylglycerols. The activity of cholinephosphotransferase (EC 2.7.8.2), which also uses diacylglycerols as substrate, was not decreased after exposure of the hepatocytes to glucagon. This may imply that triacylglycerol synthesis can be regulated independently of phosphatidylcholine synthesis. The activity of diacylglycerol acyltransferase in microsomes isolated from a homogenate of whole liver could be reduced by preincubating the microsomes with Mg2+ (5 mM), ATP (1 mM) and 105 000 X g supernatant. The enzyme could be reactivated by incubation of the washed microsomes with a 105 000 X g supernatant in the presence of dithiothreitol (5 mM). Fluoride (50 mM) inhibited this reactivation. It is concluded that the activity of diacylglycerol acyltransferase is subject to hormonal short-term control, possibly via a phosphorylation-dephosphorylation mechanism.
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PMID:Regulation of triacylglycerol synthesis in the liver: a decrease in diacylglycerol acyltransferase activity after treatment of isolated rat hepatocytes with glucagon. 626 42

Liver plasma membrane adenylate cyclase was stimulated paradoxically by an alpha 2-adrenergic mechanism under conditions of low metal ion and low GTP concentrations. In untreated membranes, epinephrine stimulation was GTP-dependent and was mediated by beta-adrenergic receptors since it was completely blocked by propranolol, but unaffected by dihydroergocryptine. Pre-treatment of membranes to remove or reduce divalent cations and guanine nucleotides changed epinephrine stimulation to a form that was mediated by alpha 2-receptors since it was completely blocked by dihydroergocryptine, phenoxybenzamine and yohimbine, but not by propranolol or prazosin. The pre-treatment did not alter enzyme activation by isoproterenol or glucagon, alpha 2-Adrenergic stimulation of adenylate cyclase in depleted membranes required the presence in the assay of 1-2 mM Mg2+ and small amounts of exogenous GTP (less than or equal to 50 nM). Increasing the Mg2+ or GTP concentration in the assay produced a progressive reversal of epinephrine-stimulated activity from an alpha 2-adrenergic form to a predominantly beta-adrenergic form. Readdition of Ca2+ or Mg2+, but not Mn2+, into depleted membranes by incubation in the presence of metal reestablished the pattern of enzyme sensitivity to epinephrine to that seen with untreated membranes i.e., it changed from alpha 2- to beta-receptor mediation. Alterations in membrane and assay content of metal ions and GTP did not result in the activation of the enzyme by vasopressin or angiotensin II. These findings demonstrate the ability of Ca2+, Mg2+ and GTP to control the coupling of beta- and alpha 2-adrenergic receptors with liver adenylate cyclase. It is hypothesized that the cations act by regulating the interaction of the receptors with adrenergic agonists and/or the guanine nucleotide binding protein(s) which is postulated to be involved in control of the enzyme.
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PMID:Regulation of adrenergic stimulation of hepatic adenylate cyclase by divalent cations. 627 6

Guanine nucleotides were observed to modify the binding of 125I-angiotensin II to rat hepatic plasma membrane receptors. GTP and its nonhydrolyzable analogues greatly increased the dissociation rate of bound 125I-angiotensin II and altered hormone binding to the receptor under equilibrium conditions. In the absence of GTP, 125I-angiotensin II labeled both high affinity sites (Kd1 = 0.46 nM, N1 = 650 fmol/mg) and low affinity sites (Kd2 = 4.1 nM, N2 = 1740 fmol/mg). In the presence of guanine nucleotides, the affinities of the two sites were unchanged, but the number of high affinity sites decreased markedly to 52 fmol/mg. In analogous experiments using the angiotensin II antagonist, 125I-sarcosine1,Ala8-angiotensin II (125I-saralasin), guanine nucleotides minimally affected the interaction of 125I-saralasin with its receptor, increasing the dissociation rate 1.9-fold and the Kd 1.4-fold. The guanine nucleotide inhibition of agonist binding required a cation such as Na+ or Mg2+, with a maximal effect occurring at about 1 mM Mg2+. In liver plasma membranes prepared in EDTA, angiotensin II inhibited basal and glucagon-stimulated adenylate cyclase activities by 30% and 10%, respectively. Angiotensin II also caused a 40% inhibition of glucagon-stimulated cyclic AMP accumulation in intact hepatocytes, with a half-maximal effect occurring at 1 nM. The inhibition by angiotensin II of adenylate cyclase in membranes and of cAMP levels in intact cells could be reversed by the antagonist sarcosine1,Ile8-angiotensin II. Vasopressin caused a smaller 26% inhibition of glucagon-stimulated cyclic AMP accumulation. The ability of angiotensin II to inhibit cyclic AMP synthesis may provide an explanation for the observed effects of guanine nucleotides on 125I-angiotensin II binding to plasma membranes.
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PMID:The hepatic angiotensin II receptor. II. Effect of guanine nucleotides and interaction with cyclic AMP production. 627 54

An enzyme that catalyzes the stoichiometric conversion of fructose 2,6-bisphosphate into fructose 6-phosphate and inorganic phosphate has been purified from rat liver. This fructose 2,6-bisphosphatase copurified with phosphofructokinase 2 (ATP: D-fructose 6-phosphate 2-phosphotransferase) in the several separation procedures used. The enzyme was active in the absence of Mg2+ and was stimulated by triphosphonucleotides in the presence of Mg2+ and also by glycerol 3-phosphate, glycerol 2-phosphate and dihydroxyacetone phosphate. It was strongly inhibited by fructose 6-phosphate at physiological concentrations and this inhibition was partially relieved by glycerol phosphate and dihydroxyacetone phosphate. The activity of fructose 2,6-bisphosphatase was increased severalfold upon incubation in the presence of cyclic-AMP-dependent protein kinase and cyclic AMP. The activation resulted from an increase in V (rate at infinite concentration of substrate) and from a greater sensitivity to the stimulatory action of ATP and of glycerol phosphate at neutral pH. The activity of fructose 2,6-bisphosphatase could also be measured in crude liver preparations and in extracts of hepatocytes. It was then increased severalfold by treatment of the cells with glucagon, when measured in the presence of triphosphonucleotides.
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PMID:Fructose-2,6-bisphosphatase from rat liver. 628 85

N-Ethylmaleimide treatment of rat liver plasma membranes results in an adenylyl cyclase (EC 4.6.1.1) system that shows no measurable cyclizing activity but retains both an active glucagon receptor and a receptor-sensitive regulatory component N as assessed by reconstitution into cyclase-negative (cyc-) membranes from S49 murine lymphoma. Treatment of such N-ethylmaleimide-treated membranes, termed C- liver membranes, with guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S] ) and Mg2+, followed by the removal of GTP[gamma S] by washing, yields an activated N which upon mixing with cyc- S49 membranes reconstitutes the cyc- S49 membrane adenylyl cyclase in the absence of added GTP[gamma S]. It was found that GTP[gamma S] activation of the N at saturating concentrations of GTP[gamma S] is slow at low Mg2+ concentration and accelerated by increasing Mg2+ concentrations. Addition of glucagon during the activation results in a lowering of the Mg2+ requirement for full activation from 25 mM to around 10 muM and in concomitant increases in both the rate and the extent of N activation. In contrast to its dramatic effect on Mg2+ requirement, glucagon has little (less than 2-fold) effect on the GTP[gamma S] requirement of N activation. These experiments indicate that the glucagon receptor facilitates activation of N by: (i) decreasing the apparent Km of N for Mg2+, and (ii) increasing the extent of activation that can be elicited by saturating concentrations of guanine nucleotide. It is postulated that the mechanism by which Mg2+ and receptors facilitate N activation involves dissociation of n alpha activated ADP-ribosylatable subunits (with guanine nucleotide bound to them) from n beta non-ADP-ribosylatable subunits (with receptor and Mg2+ bound to them).
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PMID:Hormone receptor modulates the regulatory component of adenylyl cyclase by reducing its requirement for Mg2+ and enhancing its extent of activation by guanine nucleotides. 629 Oct 28


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