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)

The stimulatory effect of Mn2+ (1.5-fold), forskolin (1.6-fold) and low (1 microM) concentrations of GTP (1.9-fold) on the adenylyl cyclase of adipocyte membranes from obese, diabetic CBA/Ca mice was markedly enhanced compared to that seen using membranes prepared from their lean littermates. In contrast, receptor-mediated stimulation, achieved with either isoprenaline or secretin was reduced and that by glucagon abolished in membranes from diabetic animals. The levels of expression of alpha-subunits of Gi-1, Gi-2 and Gi-3 were reduced to some 49, 76 and 54%, respectively, in membranes from diabetic animals compared with those from normal animals. Levels of G-protein beta-subunits and Gs alpha-subunits were similar. Receptor-mediated inhibition of adenylate activity elicited by either nicotinic acid or prostaglandin E1 (PGE1) was of a similar magnitude in membranes from normal and diabetic animals but the inhibitory action of N6-(L-2-phenylisopropyl)adenosine (PIA) was greater in membranes from diabetic animals by about 30%. Gi function was similarly evident in membranes from both lean and diabetic animals, as assessed using low concentrations of guanylyl 5'-imidodiphosphate to inhibit forskolin-stimulated adenylyl cyclase activity. However, assessing Gi function using GTP showed marked dissimilarities in that the elevated GTP concentrations expected to occur physiologically were incapable of reversing the stimulation achieved at low concentrations of GTP in membranes from diabetic but not normal animals. The adipocytes of CBA/Ca mice, as do other animal models of insulin resistance, show lesions in adenylyl cyclase regulation, Gi function and G-protein expression.
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PMID:Alterations in G-protein expression, Gi function and stimulatory receptor-mediated regulation of adipocyte adenylyl cyclase in a model of insulin-resistant diabetes with obesity. 141 80

A guanosine 5'-[gamma-[35S]thio]triphosphate-binding activity was detergent-extracted from Trypanosoma cruzi membranes. This binding activity was co-eluted from gel-filtration columns with a factor which, in a heterologous reconstitution system, blocks glucagon stimulation of adenylate cyclase activity in liver membranes. ADP-ribosylation of these membranes by pertussis toxin eliminated this blocking capacity. Incubation of T. cruzi membranes with activated pertussis toxin and [adenylate-32P]NAD+ led to the incorporation of radioactivity into a labelled product with an apparent M(r) of approx. 43,000. Crude membranes were electrophoresed on SDS/polyacrylamide gels and analysed, by Western blotting, with GA/1 anti-alpha common, AS/7 anti-alpha t, anti-alpha i1 and anti-alpha i2 polyclonal antibodies. These procedures led to the identification of a specific polypeptide band of about 43 kDa. Another polypeptide reacting with the SW/1 anti-beta antibody, of about 30 kDa, was also detected in the membrane fraction.
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PMID:Characterization of a Gi-protein from Trypanosoma cruzi epimastigote membranes. 144 3

Pituitary adenylate-cyclase-activating polypeptide (PACAP), a novel brain-gut hormone, was isolated from ovine hypothalami and represents the latest mammalian member of the secretin-glucagon peptide family. PACAP exists in two C-terminally amidated molecular forms, PACAP(1-27) and PACAP(1-38), comprising 27 or 38 amino acid residues, respectively. In order to identify a specific receptor for PACAP, we studied binding of 125I-labelled PACAP(1-27) to plasma membranes from rat brain. We identified a single high-affinity binding site (Kd, 340 pM and Bmax, 3.34 pmol/mg), specific for synthetic PACAP(1-38) and PACAP(1-27). Hormone binding was reversible and time, protein and temperature dependent. In contrast, neither the analogues PACAP(1-23), PACAP(18-38) and PACAP(3-25), nor vasoactive intestinal peptide (VIP), secretin and growth-hormone-releasing factor (GRF) revealed significant binding at concentrations up to 1 microM. A specific receptor protein, with an apparent molecular mass of 60 kDa, was identified by means of affinity cross-linking with disuccinimidyl suberate (DSS) and ethylene glycol disuccinimidyl suberate (EGS). PACAP receptors are associated with a GTP-binding protein as determined by the influence of different nucleotides on PACAP binding. PACAP-binding activity was solubilized with the detergents 3-[(3-cholamidopropyl)dimethylammonio]2-hydroxy-1-propane sulfonate (Chapso) or Triton X-100 and was characterized as a high-molecular-mass receptor complex (400 kDa) by non-reducing size-exclusion chromatography on Sepharose CL-6B. These data imply the following: high-affinity PACAP receptors are expressed abundantly on rat-brain plasma membranes; PACAP receptors are specific for PACAP and show no affinity for VIP, secretin and GRF; the PACAP receptor molecule has an apparent molecular mass of 60 kDa; the PACAP receptor complex is associated with a GTP-binding protein.
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PMID:Characterization of a guanosine-nucleotide-binding-protein-coupled receptor for pituitary adenylate-cyclase-activating polypeptide on plasma membranes from rat brain. 166 20

We determined the extent to which ligating both maternal uterine arteries affects fetal hepatic energy and redox states in the fetal rat. Bilateral maternal uterine artery ligation on d 18 of the rat's 21.5-d gestation significantly inhibits fetal growth; sham surgery limits growth to a lesser extent. Within 12 h of surgery and persisting to d 19, small-for-gestational age (SGA) fetuses had significantly diminished ATP/ADP and adenylate charge ratios, whereas sham fetuses had values intermediate between SGA and normal. Hepatic mitochondrial redox state demonstrated similar changes. Cytosolic redox state in SGA fetuses at 12 and 24 h after surgery was significantly elevated. SGA fetuses had significantly diminished plasma insulin and elevated glucagon concentrations. On d 19 and 20, hepatic ATP/ADP and cytosolic NAD+/NADH correlated directly for sham and normal but not SGA fetuses. Alterations in glucose, insulin, and glucagon availability and hypoxia were responsible for the changes in energy and redox states. They may also have disassociated hepatic cytosolic from mitochondrial redox states and altered the equilibrium between adenine and nicotinamide nucleotides. These altered cellular functions retarded fetal growth. Newborn SGA, sham, and normal rat pups had similar hepatic ATP/ADP, cytosolic, and mitochondrial redox states at 10 and 240 min after delivery suggesting that the hypoglycemia which developed in SGA pups was not attributable to alterations in these variables.
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PMID:Intrauterine growth retardation: altered hepatic energy and redox states in the fetal rat. 229 73

Exposure of cultured hepatocytes to glucagon leads to a partial refractoriness of the adenylate cyclase both to glucagon (homologous desensitization) and to isoproterenol (heterologous desensitization). In contrast, isoproterenol produces a very strong homologous desensitization but almost no heterologous desensitization. The present study compared the pattern of the homologous and heterologous components of glucagon-induced desensitization in these cells, particularly during the first 4 hours, and examined the role of cyclic 3',5'-adenosine monophosphate (cAMP) in the mechanism of refractoriness development. The decrease in glucagon-sensitive and isoproterenol-sensitive adenylate cyclase activities were closely parallel with respect to the extent, the time course and the dose required. 8-Bromoadenosine 3',5'-monophosphate (8-Bromo-cAMP) also reduced the hormone-responsive adenylate cyclase activity, but this effect developed more slowly than the desensitization after glucagon treatment. No consistent relationship was found between cAMP levels and induction of hormone refractoriness when the cells were exposed to glucagon, isoproterenol, cholera toxin or forskolin. Furthermore, addition of 0.5 mM 3-isobutyl-1-methylxanthine) (IBMX) which strongly amplified the cAMP response, did not potentiate the glucagon-induced desensitization of either glucagon-sensitive or isoproterenol-sensitive adenylate cyclase activity. Taken together, the results suggest that homologous and heterologous desensitization of the adenylate cyclase developing after glucagon exposure occur by similar (agonist-non-specific) mechanisms which do not involve cAMP.
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PMID:Glucagon-induced refractoriness of hepatocyte adenylate cyclase: comparison of homologous and heterologous components and evidence against a role of cAMP. 247 64

The effect of chemical stimulation of the central nervous system was studied in anesthetized rats. (Bu)2 cAMP, cAMP, 5'-adenosine monophosphate (AMP), ATP, and (Bu)2 N6,O2-dibutyryl guanosine-3'5'-cyclic monophosphate sodium salt were injected directly into the third cerebral ventricle, and changes in hepatic venous plasma glucose, immunoreactive glucagon, and insulin concentrations were studied. The injection of (Bu)2cAMP (1 X 10(-8) to 5 X 10(-7) mol/microliter saline) into the third cerebral ventricle caused a dose-dependent hyperglycemia associated with increased immunoreactive glucagon. (Bu)2cAMP-induced hyperglycemia and hyperglucagonemia were inhibited by prior bilateral adrenalectomy. The injection of somatostatin (1 X 10(-9) mol) with (Bu)2cAMP (5 X 10(-7) mol) into the third cerebral ventricle abolished both (Bu)2cAMP-induced hyperglycemia and an increase of glucagon secretion. These results suggest that cAMP may act intracellularly within the central nervous system to increase hepatic glucose output, and this appears to depend on the adrenal gland. Epinephrine secreted from the adrenal gland may directly act on the liver or enhance glucagon secretion, which in turn increases hepatic glucose output.
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PMID:Increase in plasma glucose concentration after intracerebroventricular injection of N,O'-dibutyryl cyclic adenosine 3',5'-monophosphate. 287 22

Rat hepatocyte protein kinase was activated by incubating the cells with various cAMP analogs. Boiled extracts were then prepared and Sephadex G-25 chromatography was carried out. The G-25 procedure separated the analogs from cAMP since the resin had the unexpected property of binding cyclic nucleotides with differing affinities. Separation was necessary because the analogs would otherwise interfere with the sensitive protein kinase activation method developed for assay of cAMP. The cAMP analogs, but not 5'-AMP, lowered basal cAMP by 50-70%. The effect was rapid, analog concentration-dependent, and occurred parallel with phosphorylase activation, suggesting that the cAMP analogs act through cAMP-dependent protein kinase activation. A cAMP analog completely blocked the cAMP elevation produced by relatively low concentrations of glucagon, but did not block the phosphorylase response, indicating that the cAMP analog substitutes for cAMP as the intracellular activator of protein kinase. One implication of the results is that elevation of cAMP and protein kinase activity by hormones has a negative feedback effect on the cellular cAMP level.
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PMID:cAMP-dependent protein kinase activation lowers hepatocyte cAMP. 299 Dec 16

GTP-sensitive adenylate cyclases in liver membranes achieved by glucagon and by cholera toxin pretreatment displayed similar responses to added GTP in assay with respect to magnitude and sensitivity. However, their susceptibility to GTP formed during incubation from added GDP catalyzed by membrane-associated nucleoside diphosphate kinase(mNDPK) was different. Adenylate cyclase pretreated with cholera toxin was essentially unaffected by added GDP, while further addition of glucagon produced activation. GTP-stimulated adenylate cyclase activity in toxin-treated membranes was inhibited by added GDP, whereas glucagon addition reduced the inhibitory action of GDP by two orders of magnitude. Since neither pretreatment with toxin nor glucagon addition altered GTP formation by mNDPK, these observations suggest a possible presence of a mechanism by which hormone makes adenylate cyclase susceptible to the GTP formed via mNDPK for activation.
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PMID:Differential susceptibility to GTP formed from added GDP via membrane-associated nucleoside diphosphate kinase of GTP-sensitive adenylate cyclases achieved by hormone and cholera toxin. 299 47

Hepatocytes from fasted rats were used to study the effect of glucagon on intracellular free cytosolic Ca2+ ([Ca2+]i) indicated by the use of Quin-2-calcium fluorescence. It was found that, in both male and female rats, glucagon increased [Ca2+]i at a half-maximally effective concentration (Kact) of 0.3 nM, a concentration known to be half-maximal for affecting several hepatic functions. Acute chelation of extracellular Ca2+ did not obliterate the hormone effect but shortened its duration. Cyclic AMP, 5'-AMP, ADP, and ATP also increased [Ca2+]i, while adenosine 2':3'-monophosphate and 3'-AMP did not. The rise in [Ca2+]i brought about by glucagon at near physiological concentrations may be responsible for the stimulation of glutamate metabolism produced acutely by glucagon.
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PMID:Sensitivity of the response of cytosolic calcium in Quin-2-loaded rat hepatocytes to glucagon, adenine nucleosides, and adenine nucleotides. 299 89

Vasoactive intestinal peptide (VIP) and VIPergic nerve fibers are present in the ovaries of several mammalian species, suggesting a possible ovarian action of VIP. We have investigated the direct effects of synthetic porcine VIP on rat granulosa cell steroidogenesis in vitro. The cells were obtained from immature, hypophysectomized, estrogen-primed rats, and cultured in a serum-free medium for 24 h in the absence or presence of varying amounts of VIP. Medium steroids were then determined by specific radioimmunoassay. Vasoactive intestinal peptide dose-dependently stimulated progesterone, 20 alpha-hydroxypregn-4-ene-3-one (20 alpha-OH-progesterone), and estrogen production with an approximate ED50 value of 3 X 10(-8) M. Maximum steroid production induced by VIP ranged from 15% to 28% of that seen with maximal follicle-stimulating hormone (FSH) stimulation. In contrast to the ability of FSH to induce luteinizing hormone (LH) receptor formation, treatment with VIP did not increase [125I]iodo-human chorionic gonadotropin (hCG) binding to granulosa cells. The ability of several gastrointestinal peptides, having 17-44% sequence identity to VIP, to stimulate granulosa cell steroidogenesis was also tested. The most closely related peptide, PHM-27 was less effective than VIP, and the least closely related, secretin and glucagon, were ineffective at 10(-6) M. Vasoactive intestinal peptide seems to act at least partly through cyclic 3',5'-adenosine monophosphate (cAMP)-dependent processes: addition of a phosphodiesterase inhibitor significantly potentiated the VIP stimulation of granulosa cell steroidogenesis, and VIP was capable of producing a dose- and time-dependent increase in both intracellular and medium cAMP levels. Vasoactive intestinal peptide stimulation of estrogen production seemed to be a result of increased aromatase activity. The increased progesterone production was associated with increased pregnenolone production, increased rate of conversion of pregnenolone to progesterone via 3 beta-hydroxysteroid dehydrogenase, and decreased metabolism of progesterone via 20 alpha-hydroxysteroid dehydrogenase. These results indicate that VIP exerts a specific action on granulosa cells to increase estrogen and progestin production. The observed direct effects of VIP, coupled with its identification in the ovary, suggest that VIP may be a physiologically important regulator of ovarian activity.
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PMID:Vasoactive intestinal peptide: a novel stimulator of steroidogenesis by cultured rat granulosa cells. 299 97


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