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)

Glucagon and adrenaline exert their action upon the liver via the cyclic AMP synthetizing system located in the plasma membrane. The enzyme adenylate cyclase is further regulated by guanyl nucleotides. It has been recently shown that the rat liver plasma membrane system could respond to GTP by simultaneous increase in the cyclase activity in response to glucagon and by the dissociation of this hormone from its binding sites (1). Unambiguous relationship between the activating effect of GTP upon the cyclase and its action upon glucagon binding has not been determined yet (2). This problem was approached using the in vitro action of epinephrine as a model. When 1 to 100 muM GTP or DGP were added to rat liver plasma membranes isolated from adrenalectomized animals, they increased markedly the response of the cyclase system to epinephrine. These effects could be observed in the absence of an ATP-regenerating system and were mimicked by 5'-guanylyl diphosphonate; GTP and GDP were the most active compounds followed by ITP, CTP and by a series of guanyl derivatives. UTP, as well as guanosine, GMP, cyclic GMP and ppGpp were inactive. Guanyl nucleotides did not increase the affinity of the cyclase system for the activating hormones, but enhanced the affinity for ATP-Mg and also the Vmax of the reaction. Finally, GTP, ATP, CTP, UTP but not GDP displaced epinephrine bound to plasma membranes by a mere chelation phenomenon. It is concluded that 1) guanyl nucleotides do not act primarily by influencing the binding of hormones to the membranes; 2) they act directly upon the catalytic subunit of the cyclase; 3) the low concentrations of GTP required for its action strongly suggest that this nucleotide plays a role in the physiological regulation of the intrahepatic cyclic AMP level.
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PMID:[Role of guanidylic nucleotides in the adenylate cyclase activity of the rat liver]. 120 15

Glucagon, a peptide hormone synthesized and secreted by alpha islet cells, regulates glucose homeostasis by several mechanisms. Using [gamma 32P]8N3GTP, a proven photoaffinity probe for GTP, a specific nucleotide binding site on human glucagon was detected that showed preference for GTP. Half-maximal saturation of photoinsertion into the polypeptide hormone was at 8-12 microM with either [alpha 32P]8N3GTP or [gamma 32P]8N3GTP. GTP protected photolabeling with an apparent kd of 15 microM, whereas ATP was less effective as a protector, exhibiting an apparent kd of about 30 microM. Maximal protection by GTP and ATP was over 90%. UTP, CTP, GDP, ADP, GMP, AMP, guanosine, adenosine, guanine, and adenine were much less effective protectors, indicating that binding is specific for purine nucleoside triphosphates, particularly GTP. Mg2+ at 150 microM enhanced photoinsertion (twofold), whereas at 2-10 mM, it inhibited photoinsertion. Both Ca2+ and Zn2+ at 0.2 mM decreased photoinsertion about 45%. Purification of chymotryptic and tryptic digests of photolabeled glucagon by reverse-phase high performance liquid chromatography (HPLC) revealed that the N-terminal peptide, HSQGTF, was the only peptide region covalently photomodified by [32P]8N3GTP. GTP, if present during photolysis, greatly reduced both photoinsertion into glucagon and the amount of radiolabeled peptide recovered on HPLC. The specificity of binding to the N-terminal region is suggestive of a physiological role for a glucagon-GTP complex in the mechanism of action of this hormone.
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PMID:Identification of the guanine binding domain peptide of the GTP-binding site of glucagon. 130 73

1. Extracellular UTP and ATP show obvious similarities in their control of several metabolic functions of rat isolated hepatocytes. 2. They have a similar time-course and concentration-dependency for the activation of glycogen phosphorylase, the generation of inositol trisphosphate (IP3), the inhibition of glycogen synthase and the lowering of adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 3. There is a similar synergism of the nucleotides with glucagon in activating phosphorylase. 4. They undergo a similar inhibition by phorbol myristic acid of their glycogenolytic effect. 5. The ATP and UTP effect on IP3 levels are not additive. 6. It is tentatively concluded that UTP and ATP use a common receptor.
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PMID:Extracellular ATP and UTP exert similar effects on rat isolated hepatocytes. 155 36

We have studied the action of a series of vasoactive and antispasmodic agents on the intrahepatic vasoconstriction induced by adrenaline in the isolated perfused liver of rabbits. The arterial and portal venous resistance, oxygen consumption, liver weight and bile flow were investigated. The drugs used were as follows: nonspecific alpha-adrenergic antagonists (DH-ergocristine, dibenamine, phenoxybenzamine), vasodilators with a direct miscellaneous action (theophylline, papaverine, dipyridamole, glucagon, Aiu-cor by Instituto Gentilli, Italy [inosine, ATP, IPI, UTP]) and antispasmodics (piperylone, tropenziline, noraminophenazone). Adrenaline increased arterial and portal venous resistance followed by a diminution of oxygen consumption, liver weight and bile flow. alpha-Adrenergic antagonists inhibited the effects of adrenaline on portal venous resistance and oxygen consumption and especially the effects on hepatic arterial resistance. The most potent agent was phenoxybenzamine. In contrast to alpha-adrenoceptor blockade, the effects of other vasoactive agents were without a sustained influence on hepatic arterial resistance (excepting those of glucagon and dipyridamole). Some of them were effective as antagonists on responses in the portal venous bed (papaverine, Aiu-cor). Moreover, there were drugs exerting an enhancement of the vasoconstrictor responses of hepatic artery to low concentrations of adrenaline with no effect on the portal venous bed (piperylone, tropenziline). Theophylline and noraminophenazone exerted no effect either on the arterial or portal venous bed. No vasodilator agent antagonized the changes of the bile flow after adrenaline administration.
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PMID:A study of the inhibition of adrenaline-induced vasoconstriction in the isolated perfused liver of rabbit. 222 14

In primary cultures of adult rat hepatocytes, transcription of the albumin gene, measured as incorporation of [alpha-32P]UTP into mRNA in isolated nuclei, decreased dramatically during culture without addition of serum and hormone, becoming almost negligible 10 h after plating. Of the hormones tested, dexamethasone (0.1 microM) prevented this decrease and restored the transcription within 2 h to the same level as that before culture. The half-maximum dose of dexamethasone for induction of transcription of the albumin gene was about 30 nM. The in vitro finding that expression of the albumin gene is strictly regulated by glucocorticoid was confirmed by an in vivo experiment in adrenalectomized rats showing that the transcription decreased markedly 14 days after adrenalectomy, but was restored rapidly by administration of hydrocortisone. This finding was also supported by identification of a glucocorticoid regulatory sequence from -50 to -62 base pairs between the TATA box and CAT box upstream of the 5'-end of the albumin gene. Cycloheximide inhibited the induction of transcription of the albumin gene by dexamethasone, suggesting that a rapidly induced mediator protein, which is also regulated by glucocorticoid, is involved in the induction of albumin gene expression by glucocorticoid. The albumin gene was also regulated by various other hormones besides glucocorticoid. Glucagon markedly enhanced the transcription induced by dexamethasone, although glucagon alone had no effect. Conversely, epinephrine suppressed stimulation of expression of the albumin gene by dexamethasone. Insulin and triiodothyronine had no effect on transcription of the albumin gene. From these findings we conclude that expression of the albumin gene depends strictly on glucocorticoid, and this dependence is modulated by other hormones.
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PMID:Glucocorticoid-dependent expression of the albumin gene in adult rat hepatocytes. 378 47

Specific binding sites for vasoactive intestinal peptide were characterized in plasma membranes from rat intestinal epithelial cells. At 30 degrees C, the interaction of 125I-labelled peptide with intestinal membranes was rapid, reversible, specific and saturable. At equilibrium, the binding of 125I-labelled peptide was competitively inhibted by native peptide in the 3 . 10(-11)--3 . 10-(7) M range concentration. Scatchard analysis of binding data suggested the presence of two distinct classes of vasoactive intestinal peptide binding sites: a class with a high affinity (Kd = 0.28 nM) and a low capacity (0.8 pmol peptide/mg membrane protein) and a class with a low affininty (Kd = 152 nM) and a high capacity (161 pmol peptide/mg membrane protein). Secretin competitively inhibited binding of 125I-labelled peptide but its potency was 1/1000 that of native peptide. Glucagon and the gastric inhibitory peptide were ineffective. The guanine nucleotides, GTP and Gpp(NH)p inhibited markedly the interaction of 125I-labelled peptide with its binding sites, by increasing the rate of dissociation of peptide bound to membranes. The other nucleotides triphosphate tested (ATP, ITP, UTP, CTP) were also effective in inhibiting binding of 125I-labelled peptide to membranes but their potencies were 1/100--1/1000 that of guanine nucleotides. The specificity and affinity of the vasoactive intestinal peptide-binding sites in plasma membranes prepared from rat intestinal epithelial cells, which is in agreement with an adenylate cyclase highly sensitive to the peptide recently characterized in these membranes (Amiranoff, B., Laburthe, M., Dupont, C. and Rosselin, G. (1978) Biochim. Biophys. Acta 544, 474--481) further argue for a physiological role of the peptide in the regulation of intestinal epithelial function.
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PMID:Characterization of specific binding sites for vasoactive intestinal peptide in rat intestinal epithelial cell membranes. 735 Sep 25

Angiotensin II stimulates the hepatic synthesis and secretion of angiotensinogen, the substrate of renin. In the present study performed on freshly isolated rat hepatocytes we demonstrate that this effect of angiotensin II is mainly related to a transient inhibition of adenylylcyclase. Agents known to decrease intracellular cAMP (angiotensin II, vasopressin, guanfacine) or the cAMP-antagonist Rp-adenosine-3',5'-cyclic phosphothioate stimulated, whereas cAMP-stimulating agents (isoproterenol, forskolin, glucagon) or the cAMP-agonist Sp-adenosine-3',5'-cyclic phosphothioate inhibited angiotensinogen synthesis. In contrast, all agents known to affect intracellular concentrations of calcium, as confirmed in Fura-2-loaded hepatocytes (Bay K 8644, calcimycin, calmidazolium, ionomycin, or methoxamine) failed to influence the synthesis of angiotensinogen. The inhibitory effect of angiotensin II as well as the stimulatory effect of glucagon on cAMP were inversely related to angiotensinogen mRNA and angiotensinogen secretion over a wide concentration range of both peptides. Both the angiotensin II-dependent inhibition of cAMP and the angiotensin II-induced increase in angiotensinogen mRNA were abolished by a pertussis toxin pretreatment. In hepatocyte membranes, pertussis toxin ADP-ribosylated a single protein (approximately 41 kDa) probably representing the alpha-subunit of the Gi-protein, coupling inhibitory receptors to adenylylcyclase. We further show that the increase of angiotensinogen mRNA and secretion mainly represents the result of mRNA stabilization, since in a nuclear run-on assay, angiotensin II pretreatment of hepatocytes does not significantly alter the rate of [32P]UTP incorporation into angiotensinogen mRNA, whereas angiotensin II prolonged the half-life of angiotensinogen mRNA in transcription-arrested as well as in [3H]uridine pulse-labeled hepatocytes about 2.5-fold from 80 to 190 min. It is concluded that angiotensin II induces an increase in angiotensinogen synthesis in hepatocytes by stabilizing of angiotensinogen mRNA and that this effect is mediated through inhibition of adenylylcyclase.
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PMID:Angiotensin II stimulates the synthesis of angiotensinogen in hepatocytes by inhibiting adenylylcyclase activity and stabilizing angiotensinogen mRNA. 822 73

1. ATP exerts multiple receptor-mediated effects on isolated hepatocytes: glycogenolysis through the activation of glycogen phosphorylase (cAMP-independent, IP3/calcium-mediated), inactivation of glycogen synthase, inhibition of the glucagon effect on cAMP, activation of phospholipase D. The fact that some of these effects can be selectively altered and that they are not, or differently, reproduced by some other analogues of ATP, suggests the presence of more than one receptor. (i) Pertussis toxin abolishes the anti-glucagon effect of ATP without affecting its glycogenolytic effect. (ii) Single cell calcium measurements reveal major differences between ATP and ADP, (iii) 2MeSATP and ADP beta S, in clear contrast to ATP, barely increase the levels of IP3 and their glycogenolytic effects is completely blocked by phorbol ester treatment of hepatocytes. (iv) 2MeSATP differs from ADP beta S since it has no anti-glucagon effect. 2. Effects of UTP on isolated hepatocytes so far do not show any difference with effects of ATP, suggesting interaction with the same receptor(s). 3. It is proposed that liver plasma membranes contain (at least) three different receptors mediating (a) the activation of phospholipase C, (b) the activation of phospholipase D and (c) the inhibition of adenylate cyclase.
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PMID:The complex interaction of ATP and UTP with isolated hepatocytes. How many receptors? 848 12

We have monitored whole-cell and single channel ATP-sensitive K+ (KATP) currents in isolated rat glucagon-secreting pancreatic A-cells. Tolbutamide produced a concentration-dependent decrease in the whole-cell KATP conductance (Ki = 6 microM) and initiated action potential firing. The K+ channel opener diazoxide, but not cromakalim or pinacidil, inhibited electrical activity and increased the whole-cell K+ conductance fourfold. ATP applied to the intracellular face of the membrane inhibited KATP channel activity with a Ki of 17 microM, an effect that could be counteracted by Mg-ADP and Mg-GDP. GTP and UTP did not affect KATP channel activity. Phosphatidylinositol 4,5-bisphosphate activated KATP channels inhibited by ATP after a delay of 90 s. In situ hybridisation demonstrated the expression of the mRNA encoding KATP channel subunits Kir6.2 and SUR1 but not Kir6.1 and SUR2. We conclude that rat pancreatic A-cells express KATP channels with the nucleotide-, sulphonylurea- and K+ channel-opener sensitivities expected for a channel formed by Kir6.2 and SUR1 subunits.
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PMID:Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells. 1051 34

Betaine, taurine, and inositol participate as osmolytes in liver cell volume homeostasis and interfere with cell function. In this study we investigated whether osmolytes are also released from the intact liver independent of osmolarity changes. In the perfused rat liver, phagocytosis of carbon particles led to a four- to fivefold stimulation of taurine efflux into the effluent perfusate above basal release rates. This taurine release was inhibited by 70-80% by the anion exchange inhibitor DIDS or by pretreatment of the rats with gadolinium chloride. Administration of vasopressin, cAMP, extracellular ATP, and glucagon also increased release of betaine and/or taurine, whereas insulin, extracellular UTP, and adenosine were without effect. In isolated liver cells, it was shown that parenchymal cells and sinusoidal endothelial cells, but not Kupffer cells and hepatic stellate cells, release osmolytes upon hormone stimulation. This may be caused by a lack of hormone receptor expression in these cells, because single-cell fluorescence measurements revealed an increase of intracellular calcium concentration in response to vasopressin and glucagon in parenchymal cells and sinusoidal endothelial cells but not in Kupffer cells and hepatic stellate cells. The data show that Kupffer cells release osmolytes during phagocytosis via DIDS-sensitive anion channels. This mechanism may be used to compensate for the increase in cell volume induced by the ingestion of phagocytosable material. The physiological significance of hormone-induced osmolyte release remains to be evaluated.
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PMID:Release of osmolytes induced by phagocytosis and hormones in rat liver. 1066 46


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