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 effect of myelin basic protein on insulin and glucagon secretion from rat pancreatic islets was studied in vivo and in vitro. The myelin basic proteins isolated from bovine, human and rat brains all stimulated insulin secretion in a similar fashion. In a static incubation of isolated pancreatic islets, myelin basic protein at doses of 15.6-250 micrograms in a 0.5-ml reaction volume (1.7 X 10(-6) to 2.7 X 10(-5) M) significantly stimulated hormone release. Maximal stimulation, obtained at the 250-micrograms dose, was 6.5-fold greater than control for insulin secretion and 6.7-fold greater than control for glucagon secretion. In the case of glucagon no saturation was observed, but saturation was obvious for insulin release at doses of myelin basic protein of 62.5-250 micrograms, larger doses causing permeabilization of the islet membranes as indicated by leakage of acid phosphatase. At a 100-micrograms dose the time course of insulin secretion induced by myelin basic protein indicated a fast initial release, and after the first 2 h only a little more insulin was released. At the lower doses of myelin basic protein (11 and 33 micrograms) the secretion rate was nearly constant after the first hour. Significant stimulation of glucagon release by myelin basic protein was seen after 60 min, the rate of release being roughly constant at 33- and 100-micrograms doses thereafter. At the 11-micrograms dose significant stimulation of hormone release was observed only after a 4-h incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myelin basic protein stimulates insulin and glucagon secretion from rat pancreatic islets in vitro and in vivo. 170 May 78

The insulinotropic and glucagon-releasing activity of acid extracts of rat hypothalami were tested in two bioassay systems using short-time incubation of isolated rat pancreatic islets and a rat insulinoma (RIN) cell line. Release of insulin and glucagon into the incubation medium was measured by radioimmunoassay. The major insulin-releasing and glucagon-releasing activity eluted in a broad zone in Sephacryl S-200 gel filtration in 30% acetic acid corresponding to the molecular weights between approximately 10 and 40 kD. The highest activity was eluted in a zone corresponding to 14 kD and was purified to homogeneity by means of two steps of reversed-phase HPLC. Amino acid analysis and SDS polyacrylamide gel electrophoresis indicated that the biologically active material was the rat small (myelin) basic protein characterized previously by Dunkley & Carnegie (1974). The purified rat hypothalamic material showed insulinotropic and glucagon-releasing activity indistinguishable from that of purified porcine myelin basic protein, and lost its insulinotropic activity when incubated with anti-myelin basic protein immunosorbent. We conclude that the major insulin-releasing and glucagon-releasing activity in acid extracts of the high-molecular-weight fractions of rat hypothalami is myelin basic protein.
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PMID:Myelin basic protein present in the acid extracts of rat hypothalami releases insulin and glucagon from isolated rat pancreatic islets. 246 73

The microsomal brush-border fraction of rat renal tissue contains enzymatic activity, optimally active at pH 9, that is capable of degrading human myelin basic protein (BP) peptide 43-88. In the present study, this degradation and the effect on it of selected drugs and hormones were examined further. Of the substances tested, 10(-2) M chloroquine and 10(-5) M ACTH 1-24 were found to be the most effective inhibitors followed by 10(-5) M ACTH 1-39; parathormone, glucagon and insulin were found to be inhibitors an order of magnitude weaker than ACTH 1-24. Hydrocortisone, dexamethasone, maleic acid and ACTH 4-10 were found to have minimal or no inhibitory effect on the peptide degrading activity. Gel filtration of the degradation products indicated that the rate of degradation of BP peptide 43-88 at pH 9 had been retarded by ACTH 1-24. These studies indicate that the clearance and catabolism of this peptide may be altered by available therapeutic agents.
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PMID:Hormonal and drug effects on the degradation of human myelin basic protein peptide 43-88 by alkaline proteolytic activity in the rat kidney. 258 80

Calmodulin, a ubiquitous Ca2+-binding regulatory protein, is phosphorylated exclusively on tyrosine-99 in an insulin-dependent manner by wheat germ lectin-purified preparations of insulin receptors from rat adipocyte plasma membranes. Calmodulin is phosphorylated in the presence of polylysine, histone Hf2b, and protamine sulfate, but not in the absence of these cofactors or in the presence of other basic compounds known to interact with calmodulin, such as mellitin, myelin basic protein, chlorpromazine, trifluoperazine, substance P, glucagon, polyarginine, mastoparin, beta-endorphin, spermine, spermidine, and putrescine. The incorporation of 32P into calmodulin, expressed in terms of moles of phosphate per moles of calmodulin and assayed at calmodulin concentrations of 1.2 and 0.06 microM, is 0.023 + 0.002 and 0.046 + 0.006, respectively. This low stoichiometry is likely due to the relative impurity of the receptor preparation, as similar studies not shown here, using highly purified human insulin receptors, yield a stoichiometry of 1 mol phosphate/mol calmodulin. The time course of phosphorylation is characterized by a short initial lag phase of approximately 5 min, a rapid linear rate from approximately 5 to 40 min, with a steady state of 32P incorporation being approached at approximately 60 min. The K0.5 for ATP is 104 + 18 microM. Phosphorylated calmodulin is partially purified by HPLC on a C4 column using a trifluoroacetic acid/acetonitrile gradient solvent system. Phosphoamino acid analysis and limited thrombin digestion were used to determine that the site of insulin-induced phosphorylation of calmodulin is exclusively on tyrosine-99 regardless of the basic protein cofactor used. Phosphorylated calmodulin does not exhibit the characteristic Ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. Thus, the tyrosine phosphorylation of calmodulin represents a potentially important post-translational modification altering calmodulin's ability to regulate a variety of enzymes involved in growth, differentiation, and metabolic regulation.
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PMID:The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. 341 47

The interaction of glucagon, human parathyroid hormone-(1-34)-peptide and salmon calcitonin with dimyristoylphosphatidylglycerol (DMPG) and with dimyristoylphosphatidylcholine (DMPC) was studied as a function of pH and temperature. The effect of lipid on the secondary structure of the peptide was assessed by circular dichroism and the effect of the peptide on the phase transition properties of the lipid was studied using differential scanning calorimetry. Some peptides interact more strongly with anionic than with zwitterionic phospholipids. This does not require an overall positive charge on the peptide. Increased thermal stability is observed in complexes formed between cationic peptides and anionic lipids. Particularly marked effects of glucagon and human parathyroid hormone-(1-34)-peptide on the phase transition properties of DMPG at pH 5 have been observed. The transition temperature is raised over 10 degrees C at a lipid/peptide molar ratio of less than 30:1 and the transition enthalpy is increased over 2-fold. These effects do not occur with any basic peptide and were not observed with metorphinamide, molluscan cardioexcitatory neuropeptide or myelin basic protein. The results demonstrate that certain peptides can affect the phase transition properties of lipids in a manner similar to divalent cations. The overall hydrophobicities of these peptides can be evaluated by their partitioning between aqueous and organic solvents. None of the above three peptide hormones partition into the organic phase. However, a closely related peptide, human calcitonin, does exhibit substantial partitioning into the organic phase. Nevertheless, human calcitonin has a weaker interaction with both DMPC and DMPG than does salmon calcitonin. The effects of human calcitonin on the phase transition of DMPC are qualitatively different from those of salmon calcitonin in that the human form more readily eliminates the pretransition but causes less change in the main transition. Like overall charge, overall hydrophobicity is not an overwhelming factor in determining the ability of peptides to interact with phospholipids but rather more specific interactions are required for strong complexes to form.
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PMID:A comparison of the interaction of glucagon, human parathyroid hormone-(1-34)-peptide and calcitonin with dimyristoylphosphatidylglycerol and with dimyristoylphosphatidylcholine. 409 81

Calmodulin (CaM) binding by turkey gizzard myosin light chain kinase (MLCK) causes subtle changes in the fluorescence emission and polarization excitation spectra of the enzyme. Fluorescence experiments using 9-anthroyl-choline (9AC), which competes with ATP in binding, demonstrate mutually stabilizing interactions between the CaM and ATP binding sites corresponding to delta G = -0.6 to -0.7 kcal/mol. Fluorescence titrations in the presence of 9AC or 5,5'-bis[8-(phenylamino)-1-naphthalenesulfonate] confirm the stoichiometry of 1 mol of CaM/MLCK. Phosphorylation of MLCK has no effect on either the protein fluorescence or the binding of ATP and 9AC. The dissociation constant for the MLCL-CaM complex is increased approximately 500-fold on phosphorylation. Values of Kd for the phosphorylated enzyme range from 0.5 to 1.1 microM in 0.2 N KCl, pH 7.3, 25 degrees C. We showed competition between MLCK and other CaM binding proteins and peptides by using both fluorescence and catalytic activity measurements. Competition for CaM occurs with ACTH, beta-endorphin, substance P, glucagon, poly(L-arginine), myelin basic protein, troponin I, and histone H2A. Phosphorylation of the last three proteins by the adenosine cyclic 3',5'-phosphate dependent protein kinase diminishes their ability to compete. Phosphorylation of MLCK by the protein kinase gives 0.95 +/- 0.04 and 2.2 +/- 0.4 mol of incorporated 32P in the presence and absence of CaM, respectively. These stoichiometries agree with those recently reported [Conti, M. A. & Adelstein, R. S. (1981) J. Biol. Chem. 256, 3178].
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PMID:Functional interactions between smooth muscle myosin light chain kinase and calmodulin. 689 95

In order to clarify insulinotropic effects of the myelin basic protein (MBP) we studied mode of association and distribution of MBP in the pancreatic islets and tested the insulin-releasing activity of various MBP peptides. Rat pancreatic islets were first stimulated in a static incubation with 10 microM bovine MBP (bMBP) at a substimulatory (3.5 mM) glucose concentration. The islets exposed to MBP released significantly more insulin and glucagon in a second incubation in the absence of added stimulant and in the presence of 11.5 mM arginine than the incubated, non-stimulated islets and islets initially stimulated with 15 mM glucose. Response to stimulation with 15 mM glucose in the second incubation by islets exposed first to MBP was impaired compared to incubated, non-stimulated islets. Immunoelectron microscopy showed that MBP had entered into the islet cells and associated with membranes of intracellular vacuoles, most of which represented enlarged, often fused insulin granules. MBP was also present at the islet edge and in the intercellular spaces. Of the purified MBP peptides of sizes of 4.8-13.6 kDa, produced from the digestion with brain acid proteinase and with pepsin and covering the entire bMBP sequence, only the large peptides (1-88, 9.8 kDa and 43-169, 13.6 kDa) stimulated insulin secretion significantly. Heterogeneous peptide mixtures, obtained from a time-course digestion of bMBP by myelin calcium-activated neutral protease, consisting of peptides of approximate molecular weights of 8-11 kDa and larger, also stimulated insulin release. The glucagon-releasing activity of MBP peptides was low and followed the same pattern as the insulin-releasing activity. The present results suggest that MBP-induced fusion of the membranes of hormone granules is involved in MBP-induced insulin release. The hormone-releasing activity of the large peptides in addition to that of the intact molecule is explained as being due to the ability of these peptides to associate with membranes. MBP-induced hormone release and related effects could be associated with neuropathological conditions such as stroke and multiple sclerosis.
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PMID:Evidence supporting membrane fusion as the mechanism of myelin basic protein-induced insulin release from rat pancreatic islets. 749 48

The central nervous system myelin basic protein (MBP) stimulates the release of several peptide hormones including insulin and glucagon. This could be associated with the development of hyperglycaemia in neurological disorders such as stroke, in which MBP is known to leak into blood circulation. In the present study the mechanism of insulin and glucagon release was investigated by using short-term incubation of isolated rat pancreatic islets. Incubation with MBP in the absence of Ca2+ resulted in approx. 11-fold stimulation of insulin and glucagon release. The stimulation dwindled with increasing Ca2+ concentration and was 6.5-fold at 0.5 mM and 2-fold at 2.5 mM Ca2+. When MBP and glucose at various concentrations were simultaneously present in the incubation mixture, stimulation of insulin release was the sum of the stimulation induced by these two agents separately both at the 0.5 and 2.5 mM Ca2+ concentrations. Glucose at concentrations of 10 or 15 mM did not suppress MBP-stimulated glucagon release. Caffeine-evoked increase in intracellular Ca2+ was without effect on MBP-stimulated insulin or glucagon release but enhanced glucose-induced insulin release. The Ca2+ channel blocker diltiazem had no effect on MBP-stimulated insulin release at concentrations where glucose-stimulated release was inhibited. Ruthenium red inhibited both MBP- and glucose-stimulated insulin release as well as MBP-induced glucagon release. Staurosporine (inhibitor of protein kinase C) had no effect on MBP-induced insulin release, although it partially inhibited glucose-stimulated release. Maleylation of MBP abolished its insulin- and glucagon-releasing activity by approx. 90%. These results suggest that MBP exerts its insulin-releasing effect by mechanisms different from those of glucose-stimulated insulin release and does not require Ca2+ channels or protein kinase C. The relation of MBP-induced insulin and glucagon release to Ca2+ concentration is probably explained by enhanced self-aggregation of MBP or by increased ability of MBP to interact with islet cell membranes in the absence of Ca2+, or both. It is concluded that MBP-induced hormone release appears to be mediated by membrane fusion and oligomerization of MBP. The mechanism thus resembles that of various toxins and other cytotoxic agents.
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PMID:Mechanism of the myelin basic protein-induced insulin and glucagon release from isolated rat pancreatic islets. 754 15

Activation of the mitogen-activated protein kinase (MAP kinase) isoforms ERK1 and ERK2 was investigated in rat adipocytes. Kinase activities were measured by using myelin basic protein as substrate after the isoforms were resolved by Mono Q chromatography or by immunoprecipitation with specific antibodies. Insulin increased the activity of both isoforms by 3- to 4-fold. The beta-adrenergic agonist isoproterenol was without effect in the absence of insulin but markedly reduced the increases in ERK1 and ERK2 activities produced by the hormone. MAP kinase activation was also attenuated by forskolin and glucagon, which increase intracellular cAMP, and by dibutyryl-cAMP, 8-bromo-cAMP, and 8-(4-chlorophenylthio)-cAMP. Thus, increasing cAMP is associated with decreased activation of MAP kinase by insulin. Forskolin also inhibited activation of MAP kinase by several agents (epidermal growth factor, phorbol 12-myristate 13-acetate, and okadaic acid) that act independently of insulin receptors. Moreover, forskolin did not inhibit insulin-stimulated tyrosine phosphorylation of the insulin receptor substrate IRS-1. Therefore, the inhibitory effect on MAP kinase did not result from compromised functioning of the insulin receptor. The inhibitory effect was not confined to adipocytes, as forskolin and dibutyryl-cAMP inhibited the increase in MAP kinase activity by phorbol 12-myristate 13-acetate in wild-type CHO cells. In contrast, these agents did not inhibit MAP kinase activity in mutant CHO cells (line 10248) that express a cAMP-dependent protein kinase resistant to activation by cAMP. Our results suggest that activation of cAMP-dependent protein kinase represents a general counter-regulatory mechanism for opposing MAP kinase activation.
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PMID:Increasing cAMP attenuates activation of mitogen-activated protein kinase. 769 90

Following acute central nervous system myelin injury, immunoreactive myelin basic protein (MBP) has been detected in the cerebrospinal fluid, blood and urine. In order to clarify the fate of MBP in the circulation, distribution and degradation of intravenously injected bovine MBP was followed in anaestethized rats for 5 to 240 min by using 125I-labelled MBP. Five minutes after injection of a dose of 60-400 ng of MBP, 44% of the label was recovered in the liver, 6.3% in the kidneys, 4.7% in the lungs and 15% in the blood circulation, the corresponding figures at a dose of 0.8 mg being 51, 7.4, 0.8 and 22%. The liver discarded the label fastest, 3% of the dose remaining 4 h after injection. The amount of label in urine increased simultaneously, the recovery at 4 h being 5.5% of the lower and 4.2% of the higher MBP dose. The percentage of total dose of the label per gram of tissue at 5 min (= distribution percentage, DP-5) was 3-4% in the liver and kidney and 1.6% in the spleen. The label content in the pancreas was increased at 15-60 min, compared to the DP-5 of 0.3% with a two-fold maximum at 30 min. The duodenum concentrated MBP in a similar manner as the pancreas but not as extensively. The DP-5 of 0.1% in the thymus was concentrated two-fold with a maximum at 60 min. A slight concentration occurred in the heart. The DP-5 of 0.03% in muscle, testis and brain was concentrated 3-fold at 60 min, 3.6-fold at 60-240 min and 2-fold at 30-60 min in the aforementioned tissues, respectively. In spite of degradation of the label in tissues, the distribution of high molecular weight (HMW = TCA-precipitable) MBP was similar. Other experiments showed that the kidney, lung and duodenum contained most of the HMW MBP at 20 h. Upon continuous release of MBP, the pancrease, thymus, duodenum, muscle and testis would thus cumulatively concentrate MBP, and the kidney, lung and duodenum would be quantitatively most affected. MBP was previously shown to enter into cells of pancreative islets and to stimulate insulin and glucagon release. It could have biological effects in other tissues as well. These effects could explain some peripheral symptoms present in neurological disorders.
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PMID:Disappearance of 125I-labelled myelin basic protein from blood circulation and its degradation and accumulation in various tissues in rats. 888 Jun 87


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