UNIPROT:P01275 - FACTA Search

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Query: UNIPROT:P01275 (glucagon)
26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of parathyroid hormone (PTH) on plasma and urinary adenosine 3',5'-monophosphate (cyclic AMP) levels were studied in normal subjects. Under basal conditions normal adults have plasma concentrations of cyclic AMP ranging from 10 to 25 nmoles/liter and excrete from 1.5 to 5 mumoles of cyclic AMP per g of urinary creatinine. About one-half to two-thirds of the cyclic AMP excreted in the urine is derived from the plasma by glomerular filtration, and the remainder is produced by the kidney. Renal production of cyclic AMP is partly under the control of PTH. It can be suppressed by infusions of calcium and stimulated by infusions of the calcium chelating agent, EDTA. Infusions of PTH in doses up to 10 mU/kg per min were associated with dose-related increases both in urinary cyclic AMP and phosphate. Infusions of PTH in doses ranging from 20 to 80 mU/kg per min did not lead to any further increase in phosphaturia but did lead to further marked increases in urinary cyclic AMP. A modest increase in plasma cyclic AMP was noted when PTH was infused at 40 mU/kg per min. Anephric patients failed to show appreciable increases in plasma cyclic AMP in response to large doses of PTH but did show expected increases in response to glucagon. Surgical removal of parathyroid adenomas from nine patients with primary hyperparathyroidism was invariably followed by a decrease in urinary cyclic AMP, PTH, in large doses, and calcium infusion produced up to 2-fold increases in the other known naturally occurring cyclic nucleotide, guanosine 3',5'-monophosphate (cyclic GMP).
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PMID:Effects of parathyroid hormone on plasma and urinary adenosine 3',5'-monophosphate in man. 548 Aug 62

Porcine ileal mucosa was homogenized and freeze-thawed in 0.05 M NH4HCO3 + 0.01 M EDTA + 1 mM benzamidine hydrochloride at pH 8.6. Subsequent stepwise precipitation with (NH4)2SO4 followed by fractionation on Sephadex G-50 medium and G-50 fine eluted with alkaline buffer and final fractionation on G-50 superfine in 1.0 M acetic acid yielded a pure protein of 13,000 daltons as determined by sodium dodecyl sulfate electrophoresis. The amino acid composition of the protein has been determined and it contains 126 residues with no tryptophan detectable. Tryptic peptide maps demonstrate that the protein does not contain glucagon and RIA of the peptide did not detect any immunoreactive glucagon or gastrin. The isoelectric point is 6.4. The intact protein is resistant to Edman degradation and the partial N-terminal sequences of two CNBr fragments are: Lys-Arg-Leu-Ala-Leu ...., Glu-Gly-Gly-Thr-Val-Val-Val-Asn-Ser.... The C-terminal residue, alanine was determined using carboxypeptidase Y. The isolated peptide, in the range of 10(-15)-10(-9) M stimulated oxyntic cell hydroxyl ion production in sections of guinea pig gastric fundus. The dose response was linear with biphasic peaks at 10(-14) and 10(-9) M and the maximal response to the peptide was equal to that observed with gastrin. The addition of either atropine (10(-5) M) or cimetidine (10(-5) M) with the peptide (10(-14) M) caused greater than 50% inhibition of oxyntic cell stimulation (P less than 0.005). This peptide is a potent stimulator of the oxyntic cell and its effect is inhibited by muscarinic cholinergic and H2 receptor blockers. Hence, it represents a significant component of the physiological enterooxyntin effect observed in response to intestinal meals.
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PMID:Isolation and partial characterization of an entero-oxyntin from porcine ileum. 609 Jan 3

Isolated rat liver mitochondria were incubated at 0 degrees C in a medium consisting of 225 mM sucrose, 10 mM KCl, 1 mM EDTA, 10 mM KH2PO4, 5 mM MgCl2 and 10 mM Tris-HCl, pH 7.4 (buffer 1) for 10 min, centrifuged and resuspended in 0.3 M sucrose. This treatment resulted in a stimulation of mitochondrial functions, mimicking several of the effects that follow glucagon treatment of the intact rat or isolated hepatocytes. Both phosphate and potassium are required for this effect; the addition of magnesium serves to enhance it. Mitochondrial respiration is essential for the development of the activated state as the stimulation is blocked by increasing concentrations of rotenone in the incubation. The intramitochondrial ATP/ADP ratio is increased, but when this increase was prevented by including low levels of rotenone or oligomycin in buffer 1, the stimulation of mitochondrial function was not diminished, thus demonstrating that an increased ATP/ADP ratio is not essential for activation. The rate of citrulline formation was unaffected by buffer 1 treatment unless glutamate was also included in the medium, indicating that control of this mitochondrial function differs from other functions studied.
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PMID:Hormonal regulation of mitochondrial function. Description of a system capable of mimicking several effects of glucagon. 613 97

Results from recent studies have indicated that pancreatic islet prohormone converting enzymes are membrane-associated in islet microsomes and secretory granules. This observation, along with the demonstration that proglucagon is topologically segregated to the periphery within alpha cell secretory granules in several species, led us to investigate the possibility that newly synthesized islet prohormones might be associated with intracellular membranes. Anglerfish islets were incubated with [3H]tryptophan and [14C]isoleucine for 3 h, then fractionated by differential and density gradient centrifugation. Microsome (M) and secretory granule (SG) fractions were halved, sedimented, and resuspended in the presence or absence of dissociative reagents. After membrane lysis by repeated freezing and thawing, the membranous and soluble components were separated by centrifugation. Extracts of supernatants and pellets were chromatographed by gel filtration; fractions were collected and counted. A high proportion (77-79%) of the newly synthesized proinsulin and insulin was associated with both M and SG membranes. Most of the newly synthesized proglucagons and prosomatostatins (12,000-mol-wt precursors) were also membrane-associated (86-88%) in M and SG. In contrast, glucagon- and somatostatin-related peptides exhibited much less membrane-association in SG (24-31%). Bacitracin, bovine serum albumin EDTA, RNAse, alpha-methylmannoside, N-acetylglucosamine, and dithiodipyridine had no effect on prohormone association with membranes. However, high salt (1 M KCl) significantly reduced membrane-association of prohormones. Binding of labeled prohormones to SG membranes from unlabeled tissue increased with incubation time and was inhibited by unlabeled prohormones. The pH optimum for prohormone binding to both M and SG membranes was 5.2. It is suggested that association of newly synthesized prohormones with intracellular membranes could be related to the facilitation of proteolytic processing of prohormones and/or transport from their site of synthesis to the secretory granules.
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PMID:Association of newly synthesized islet prohormones with intracellular membranes. 614 27

1 The vasodilator effects of glucagon and adenosine cyclic 3',5'-monophosphate (cyclic AMP) were evaluated in strips of rabbit renal artery contracted with noradrenaline (NA) in the absence and presence of phosphodiesterase inhibitors or calcium (Ca(2+)) antagonists.2 The vascular relaxant effect of glucagon was markedly potentiated by various concentrations of four different phosphodiesterase inhibitors (papaverine, theophylline, 3-isobutyl-l-methylxanthine (IBMX) and indomethacin), while that of cyclic AMP was potentiated by only two of them (papaverine and indomethacin) and inhibited by the others (theophylline and IBMX).3 Amongst the four phosphodiesterase inhibitors, IBMX (10 mug/ml) was found to produce the largest potentiation (e.g. the sensitivity increased by a factor of 10) of glucagon-induced vascular relaxations (ED(50) of glucagon in the presence of IBMX = 9.2 +/- 1.0 ng/ml).4 Ca(2+) antagonists such as verapamil and SKF 525A produced a dose-dependent inhibition of the vasodilator action of glucagon. Verapamil (2.5 mug/ml) also antagonized cyclic AMP-induced vascular relaxations.5 The vasodilator effect of verapamil was inhibited dose-dependently by raising the concentration of extracellular Ca(2+) from 0.05 to 0.2 g/l (or 1.25 to 5.0 mM) while those elicited by glucagon or cyclic AMP were not influenced, thus suggesting that the latter two drugs do not interfere with Ca(2+) influx.6 Disodium edetate (Na(2)EDTA, 210 to 840 mug/l) produced a dose-dependent vasodilator effect which was attributed to the facilitation of Ca(2+) extrusion from the smooth muscle cells and/or Ca(2+) binding to the cell membrane. The relaxation produced by Na(2)EDTA was significantly blocked by verapamil (10 mug/ml) or SKF 525A (10 mug/ml).7 The results were taken as an indication that glucagon produces at least a fraction of its vasodilator effect by promoting Ca(2+) extrusion from the vascular smooth muscle cells and/or Ca(2+) binding to or sequestration into intracellular sites, presumably via a cyclic AMP-dependent mechanism.
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PMID:Studies on the mechanism of action of glucagon in strips of rabbit renal artery. 615 33

The effects of glucagon, gastric inhibitory peptide (GIP) and somatostatin on the generation of cyclic AMP have been studied under basal and histamine- or secretin-stimulated conditions in tubular gastric glands isolated by means of EDTA from the rat fundus and antrum. Four types of cell could be identified by electron microscopy; namely, parietal, mucous, peptic and some endocrine cells with a good morphological preservation of the cellular topography as seen in the intact mucosa. Immunoreactive somatostatin was found in antral glands (210 +/- 16 ng/g cell, wet wt., n = 9) as well as in fundic glands, but in smaller concentration (50 +/- 8 ng/g cell, wet wt., n = 9). (1) In rat fundic glands, glucagon, in supraphysiologic doses (3 . 10(-9) -5 . 10(-7) M), raised cyclic AMP levels 46 times above the basal. At maximally effective doses, combination of glucagon plus histamine was not additive whereas glucagon and secretin stimulations resulted in an additive response. Somatostatin (10(-10) -10(-7) M) inhibited both glucagon- and histamine-induced cyclic AMP production, whereas cimetidine specifically blocked the histaminergic stimulation. (2) In the same conditions, 10(-6)M glucagon produced a marginal effect (4-fold increase) in rat antrum, whereas GIP (10(-9) -10(-6)M) was unable to induce a significant rise of cyclic AMP production in either fundic or antral glands, or to prevent cyclic AMP production stimulated by histamine. (3) The present data do not support the view that circulating glucagon or GIP may regulate gastric secretion directly by a cyclic AMP-dependent mechanism in rat gastric glands and raise the possibility that gastric somatostatin may be the final mediator of the inhibitory actions of these hormones on acid secretion. (4) It is proposed that pancreatic glucagon acts through a receptor-cyclic AMP system which is specific for the bioactive peptide enteroglucagon ('oxyntomodulin'), probably in rat parietal cells.
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PMID:The interaction of glucagon, gastric inhibitory peptide and somatostatin with cyclic AMP production systems present in rat gastric glands. 617 56

Receptors, i.e. specific binding sites for vasoactive intestinal peptide (VIP), have been characterized in human colonic epithelial cells isolated by EDTA treatment using 125I-labeled porcine VIP. The binding was time and temperature dependent. Conditions of apparent equilibrium were obtained at 15 C after 45 min of incubation in the presence of 2.1-7.4 micrograms cell DNA-ml; these conditions minimized the degradation of the peptide and the binding sites. Native VIP competitively inhibited the binding of [125I]VIP in the range of 3 x 10(-11)-10(-7) M, and half-maximal inhibition was observed at 2 x 10(-9) M VIP. Scatchard analysis of these data was consistent with the existence of two classes of binding sites: 7.8 x 10(-9) high affinity sites/microgram DNA with a dissociation constant (Kd) of 1.4 x 10(-9) M, and 12.0 x 10(10) low affinity sites/microgram DNA with a Kd of 46 x 10(-9) M. Among the natural hormones structurally related to VIP, gastric inhibitory polypeptide (GIP) and glucagon had no effect on the binding of labeled porcine VIP. Porcine secretin inhibited [125I]VIP binding, but at doses 1000 times higher than those of porcine VIP. Studies of the coupling between the binding of VIP and the stimulation of cAMP formation indicated a nonlinear relationship between the two processes, with full activation of the cAMP-producing system with occupancy of only a limited number of the binding sites. The presence of binding sites with high affinity for VIP coupled with the cAMP production in human colonic epithelial cells support the concept that this peptide may contribute to the physiological regulation of the functions of the human colonic epithelium in normal and pathological conditions.
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PMID:Characterization of vasoactive intestinal peptide receptors in human colonic epithelial cells. 625 91

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

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 islet cell tumor, characterized by proinsulin level significantly elevated above normal human pancreas, has been found to contain insulin- and glucagon-degrading activity. Examination by chromatography on Sephadex G-75 of the degradation products formed from insulin showed A chain, and B chain rich-A chain aggregate as previously found with rat pancreatic islets. There was, however, little conversion of A chain to low molecular weight components indicating that insulinoma peptidase that has been found to degrade glucagon at about pH 6.8 degraded that A chain to a markedly lower rate. In contrast to the insulin-degrading activity, which was activated by glutathione in the presence of EDTA, the peptidase activity was not affected by the thiol compound. The activity of the peptidase was markedly inhibited by chelating agents, i.e., EDTA and o-phenanthroline, whereas chymotrypsin and trypsin inhibitors, i.e., TOS-PheCH2Cl, TOS-LysCH2Cl, soybean and pancreas trypsin inhibitor were found to have no effect.
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PMID:Thiol-protein disulfide oxidoreductase and peptidase activities in insulinoma tissue. 632 44

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