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 hydroxylation of tyrosine to dopa is the rate-limiting reaction in catecholamine biosynthesis. It has been previously reported that secretin, vasoactive intestinal peptide and peptide histidine isoleucine amide, all members of the secretin-glucagon family of peptides, increase dopa synthesis in superior cervical ganglia in vitro. We report here that two other members of this peptide family, rat growth hormone-releasing factor and helodermin H38, a component of Gila monster venom, also increase the rate of dopa synthesis, while glucagon-like peptides I and II and a number of other peptides tested produce no effect. Since analogs of cAMP also increase dopa synthesis, it is of particular interest that all of the peptides that increase catechol synthesis also raise the levels of this cyclic nucleotide in the superior cervical ganglion. Helodermin H38 stimulated the rate of dopa synthesis and the level of cAMP with similar potencies (EC50S of approximately 10 nM) and with maximal effects of two- and two-fold, respectively. By either measure, rat growth hormone-releasing factor produced a two-fold increase at 10 microM and a three- to four-fold increase at 30 microM. Analogs of peptides of the secretin-glucagon family with a deletion or modification of the N-terminal histidine were much less effective in these assays at the concentrations tested than were their parent compounds, demonstrating an important role for this amino acid in conferring activity on these peptides. In addition to increasing dopa synthesis in intact tissue, incubation of ganglia with rat growth hormone-releasing factor, secretin, vasoactive intestinal peptide or peptide histidine isoleucine amide also increased the activity of tyrosine hydroxylase measured subsequently in ganglion homogenates. Thus, the peptidergic stimulation of dopa synthesis observed in the intact superior cervical ganglion appears to be due, at least in part, to the activation of tyrosine hydroxylase. Together with previous studies, these findings support the hypothesis that certain members of the secretin-glucagon family increase catecholamine synthesis in sympathetic neurons by a cAMP-dependent activation of tyrosine hydroxylase.
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PMID:Activation of ganglionic tyrosine hydroxylase by peptides of the secretin-glucagon family: structure-function studies. 257 Mar 76

The gastroenteropancreatic (GEP) endocrine system of three reptiles, Testudo graeca, Mauremys caspica, and Lacerta lepida, was investigated by means of immunocytochemistry. Single and double immunostaining methods have demonstrated immunoreactivity for insulin, glucagon, pancreatic polypeptide (PP), somatostatin, serotonin, and peptide tyrosine tyrosine (PYY) in endocrine cells of the pancreas of the reptiles studied. Islet-like structures with insulin-immunoreactive (IR) cells surrounded by glucagon-IR cells were observed only in the splenic portion of the pancreas of M. caspica. Occasionally, somatostatin- and PP-IR cells were associated with glucagon-containing cells. Endocrine cells were also observed in the excretory ducts of the exocrine glands. Serotonin, bombesin, neurotensin, gastrin, glucagon, somatostatin, PYY, and insulin were demonstrated immunocytochemically in open-type GEP cells of the digestive tract of the animals studied. Serotonin, somatostatin, and glucagon-immunoreactive cells were the most abundant endocrine cell types. In L. lepida, PP- and peptide tyrosine tyrosine-immunoreactive cells were also frequently observed. Cells containing cholecystokinin, gastric inhibitory peptide, met- and leu-enkephalin, motilin, secretin, and vasoactive intestinal peptide could not be detected. The present work demonstrates that the reptilian GEP endocrine system is a complex structure containing most of the regulatory peptides similar in structure to those found in higher vertebrates.
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PMID:Comparative immunohistochemical study of the gastroenteropancreatic endocrine system of three reptiles. 257 25

A facet of carcinoid tumors often not recognized is their close association with other, noncarcinoid malignancies. The clinical course of two patients with multiple ileal-jejunal carcinoids and multiple other noncarcinoid malignancies is described. These patients were found to have elevated circulating levels of gastrin, bombesin, glucagon, enteroglucagon, pancreatic polypeptide, and peptide tyrosine tyrosine. These regulatory peptides have been demonstrated to promote trophic effects on the gastrointestinal tract as well as malignant tumors. We propose that the release of these bioactive hormones into the portal and systemic circulation by carcinoid tumors may play some role in their association with these multiple second tumors.
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PMID:Malignant diathesis from jejunal-ileal carcinoids. 264 19

The degradation of intracellular protein and other cytoplasmic macromolecules in liver is an ongoing process that regulates cytoplasmic mass and provides amino acids for energy and other metabolic uses early in starvation. Cellular proteins are conveniently divided into two general classes according to readily discernable differences in average rates of turnover. A short-lived class, having a half-life of approximately 10 min, comprises about 0.6% of total protein. Its degradation is not physiologically controlled, and the mechanism is probably nonlysosomal in nature. The second or long-lived group, with an average half-life 250 times greater, constitutes more than 99% of the cell's protein. By contrast, its breakdown is strongly regulated, and the site of catabolism is believed to be the vacuolar-lysosomal system. Cytoplasmic sequestration by lysosomes can be divided into two categories; macro- and microautophagy. The first is induced by amino acid and/or insulin deprivation. Amino acids are considered to be primary regulators, since they can control this process over the full range of induced proteolysis in the absence of hormones. Glucagon, cyclic AMP, and beta-agonists also stimulate macroautophagy in hepatocytes but have opposite effects in myocytes. Micrautophagy differs from the former in that the cytoplasmic "bite" is smaller and the uptake process is not acutely regulated. However, the latter does decrease during starvation in parallel with basal proteolysis, effects that might be linked to the loss of endoplasmic reticulum. The primary control of macroautophagy is accomplished through a small group of direct regulators (Leu, Tyr/Phe, Gln, Pro, Met, His, and Trp) and a specific coregulatory action of alanine. As a group, regulatory amino acids produce direct inhibitory responses in the perfused rat liver that are identical to those of the complete amino acid mixture at 0.5x and 4x (times) normal plasma concentrations. However, they lose effectiveness almost completely within a narrow zone centered at normal levels, a loss that can be abolished by the addition of alanine at its normal plasma concentration (0.5 mM). At this level, alanine does not inhibit directly. Interestingly, this zonal loss is also eliminated by insulin. Glucagon, though, specifically blocks the initial inhibition evoked by 0.5x amino acid mixtures and thus induces maximal rates of protein degradation at normal amino acid concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism and regulation of protein degradation in liver. 264 36

Short-term and long-term biological activities were studied in adult rat hepatocytes cultured in the presence of the insulin analogues des-(B26-B30)-insulinamide, [TyrB25]des-(B26-B30)-insulinamide and [HisB25]des-(B26-B30)-insulinamide. When compared to insulin, full potency of des-(B26-B30)-insulinamide has been reported in rat adipocytes and an enhanced potency has been reported for the other analogues. Steady state binding characteristics of the analogues to hepatocytes were indistinguishable from those of native insulin with half-maximal binding occurring at concentrations of about 0.8 nmol/l. Half-maximal effects for the stimulation of glycolysis and inhibition of basal and glucagon-activated glycogenolysis required identical concentrations for insulin and all 3 analogues. Induction of the key glycolytic enzymes glucokinase and pyruvate kinase as well as the inhibition of glucagon-dependent induction of phosphenolpyruvate carboxy-kinase also required identical concentrations of insulin and the 3 analogues. These data confirm that in cultured hepatocytes the C-terminal amidation of des-(B26-B30)-insulin results in a molecule with full in vitro potency. In contrast to data obtained in adipocytes, the des-(B26-B30)-insulin-amidated analogues with tyrosine or histidine substitutions at position B25 are equally as potent as native insulin in eliciting biological responses in rat hepatocyte culture.
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PMID:Biological activity of des-(B26-B30)-insulinamide and related analogues in rat hepatocyte cultures. 268 Jun 97

Using a biologically active radioligand, [Tyr(125I)10]VIP, we have identified and characterized receptors for vasoactive intestinal peptide (VIP) on membranes prepared from the rat superior mesenteric artery and bovine coronary arteries. Binding was specific, saturable, reversible and dependent on time and temperature. Scatchard analysis suggested the presence of a high and a low affinity binding site in each arterial system with the following binding constants: the rat mesenteric artery, KD = 0.22 +/- 0.02 and 13.6 +/- 7.8 nM (corresponding maximum number of binding sites, RO = 606 +/- 44 fmol/mg protein and 2.1 +/- 0.2 pmol/mg protein); bovine circumflex coronary artery, KD = 0.10 +/- 0.01 and 37.8 +/- 16.1 nM (corresponding RO = 369 +/- 65 fmol/mg protein and 2.0 +/- 0.7 pmol/mg protein); bovine left and right descending coronary arteries, KD = 0.12 +/- 0.03 and 21.3 +/- 6.4 nM (corresponding RO = 472 +/- 7 fmol/mg protein and 2.2 +/- 0.3 pmol/mg protein). The arterial VIP receptors did not recognize secretin, glucagon, apamin or bovine parathyroid hormone, and had reduced affinity for PHI, PHM and growth hormone releasing factors (GRF). These recognition properties were, by and large, similar to those seen in the bovine cerebral arteries although a between-species heterogeneity of recognition function could be deduced from the differences in the competitive binding of rat and bovine vascular VIP receptors with the corresponding species-specific GRFs.
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PMID:VIP receptors in mesenteric and coronary arteries: a radioligand binding study. 282 20

In our effort to identify the proteolytic specificity of various hemorrhagic toxins isolated from western diamondback rattlesnake venom, hemorrhagic toxin b was isolated in homogeneous form by previously published methods. Hemorrhagic toxin b hydrolyzed glucagon, producing six fragments. The proteolytic sites were identified as Thr(5)-Phe(6), Thr(10)-Ser(11), Asp(15)-Ser(16), Asp(21)-Phe(22) and Try(25)-Leu(26). When oxidized insulin B chain was used, proteolysis occurred at four sites: Asn(3)-Gln(4), His(10)-Leu(11), Tyr(16)-Leu(17) and Gly(23)-Phe(24). The proteolytic specificity of hemorrhagic toxin b is quite different from those of the nonvenom proteases such as thermomycolin, aspergillopeptidase c, alkaline protease from Aspergillus flavus, elastase, subtilisin and papain.
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PMID:Proteolytic specificity of hemorrhagic toxin b from Crotalus atrox (western diamondback rattlesnake) venom. 286 65

In the search for selective and long-acting analogs of somatostatin, nearly 200 compounds were synthesized by solid-phase methods, purified, and tested biologically. Among these octapeptides, some contained N-terminal (Formula: see text) were 177 times and 113 times more potent, respectively, than somatostatin in tests for inhibition of growth hormone release. These two octapeptides containing tyrosine and valine in positions 3 and 6, respectively, were more active and more selective than their Phe-3 and Thr-6 counterparts, D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 and D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2. D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 was also about 6 times more potent than its L-Trp-4 diastereoisomer. The analogs D-Phe-Cys-Tyr-Lys-Val-Cys-Thr-NH2 and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 showed a prolonged duration of action and were able to inhibit growth hormone release for at least 3 hr. Analogs of both Phe-3/Thr-6 and Tyr-3/Val-6 classes also suppressed the release of insulin and glucagon in rats and pentagastrin-induced secretion of gastric acid in dogs, but their potencies in these tests were much smaller than the growth-hormone-release inhibitory activity. Some of these analogs possessed antitumor activities as shown by the inhibition of growth of animal models of prostate, mammary, and ductal pancreatic tumors.
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PMID:Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. 286 90

The quantitative importance of the individual steps of aromatic amino acid metabolism in rat liver was determined by calculation of the respective Control Coefficients (Strengths). The Control Coefficient of tryptophan 2,3-dioxygenase for tryptophan degradation was determined in a variety of physiological conditions and with a range of activities of tryptophan 2,3-dioxygenase. The Control Coefficient varied from 0.75 with basal enzyme activity to 0.25 after maximal induction of the enzyme by dexamethasone. The remainder of the control for tryptophan degradation was associated with the transport of the amino acid across the plasma membrane, with only very small contributions from kynureninase and kynurenine hydroxylase. The Control Coefficients of tyrosine aminotransferase for tyrosine degradation were approx. 0.70 and 0.20 with basal and dexamethasone-induced tyrosine aminotransferase activities respectively; the Control Coefficients of the transport of the amino acid into the cell were 0.22 and 0.58 respectively. Phenylalanine hydroxylase was found to have a Control Coefficient for the degradation of phenylalanine of approx. 0.50 under conditions of basal enzyme activity; after maximal activation by glucagon, the Control Coefficient decreased to 0.12. The transport of phenylalanine was responsible for the remaining control in the pathway. These results have important implications, directly for the regulation of aromatic amino acid metabolism in the liver, and indirectly for the regulation of neuroamine synthesis in the brain.
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PMID:Quantification of the importance of individual steps in the control of aromatic amino acid metabolism. 287 85

Transport and hydrolysis of glucagon in the rabbit proximal nephron were studied. Iodinated glucagon (0.34 +/- 0.02 pg/nl, mean +/- SE) was microperfused (16.0 +/- 1.1 nl/min) in vitro through proximal straight nephron segments for 30 min. Radiolabeled material, primarily 125I-tyrosine, appeared in the bathing medium in a linear fashion as a function of time (0.406 pg glucagon X mm tubule length-1 X min-1). Hydrolysis of glucagon by proximal tubule homogenates was pH dependent, with a large peak of activity observed at pH 7.0-7.4 and a smaller one at pH 3.0. Analytical cell fractionation studies of proximal tubule cells revealed glucagon-hydrolyzing activity associated with the brush border and cytosol at pH 7.4. Less than 3% of activity was found associated with the contraluminal membrane. Substantial catabolism was observed at lysosomes on lowering the pH to 5.0. Incubation of glucagon directly in the presence of isolated renal cortical microvilli confirmed the presence of a high-capacity glucagon-degrading hydrolase. In addition to glucagon-hydrolyzing activity associated with the proximal nephron, noncortical activity was observed that was not accounted for by proximal tubule hydrolases. The data suggest several mechanisms for renal extraction of glucagon, including hydrolysis by enzymes at the brush border of the proximal tubule, prior to reabsorption of metabolites there. Conversely, enzymes associated with the contraluminal membrane of the proximal nephron probably contribute little to its hydrolysis. Nonproximal extracortical degradation of glucagon may account for its previously observed peritubular hydrolysis.
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PMID:Transport and hydrolysis of glucagon in the proximal nephron. 287 55


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