Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effect of glucagon-like peptide 1 (GLP-1)-(7-36) amide and its molecular variants GLP-1-(1-37) and GLP-1-(1-36) amide on enzymatically dispersed enriched rat parietal cells using [14C]aminopyrine accumulation as a measure of H+ production. GLP-1-(7-36) amide was 100 times more potent than GLP-1-(1-37) and GLP-1-(1-36) amide in stimulating [14C]aminopyrine accumulation. At their maximally effective concentrations, GLP-1-(7-36) amide (10(-8) M), GLP-1-(1-37) (10(-6) M), and GLP-1-(1-36) amide (10(-6) M) reached 80-90% of the response to 10(-4) M histamine. However, the peptides were 100-10,000 times more potent than histamine, which induced maximal [14C]aminopyrine accumulation at 10(-4) M. Stimulation by GLP-1 was dependent on the presence of a phosphodiesterase inhibitor and was not altered by pertussis toxin. Ranitidine failed to affect the response to the GLP-1 variants. Stimulation of H+ production by GLP-1 was accompanied by an increase in the formation of adenosine 3',5'-cyclic monophosphate (cAMP) but not by changes in phosphoinositol breakdown. In stimulating [14C]aminopyrine accumulation, the GLP-1 variants acted additively to threshold but not to maximal concentrations of histamine, suggesting that histamine and GLP-1 activate the same cAMP pool. In contrast, in anesthetized rats GLP-1-(7-36) amide (10-500 ng.kg-1.h-1) had no effect on basal and pentagastrin-stimulated acid secretion in vivo. We conclude that GLP-1 exerts a direct stimulatory effect on rat parietal cells. This potent effect is mediated by cAMP and is independent of H2 receptors. In vivo direct stimulation by GLP-1 of the parietal cells might be counterbalanced by indirect inhibitory mechanisms that are excluded in the in vitro cell system.
 ...
PMID:GLP-1-(7-36) amide, -(1-37), and -(1-36) amide: potent cAMP-dependent stimuli of rat parietal cell function. 171 82

In order to investigate the regulation of canalicular organic-anion transport, we used a hepatocyte transport assay in which canalicular secretion of a model organic anion, dinitrophenyl-glutathione (GS-DNP), was measured in the presence of stimulators and inhibitors of the Ca2+/protein kinase C (PKC) second-messenger system and of the cyclic AMP (cAMP) second-messenger system. Vasopressin (24 nM) and the phorbol ester phorbol 12-myristate 13-acetate (1 microgram/ml), both stimulators of PKC, stimulated GS-DNP efflux by 65 +/- 36% and 55 +/- 28% respectively, whereas staurosporine (10 microM), an inhibitor of PKC, inhibited efflux by 53 +/- 13%. Glucagon and forskolin, both stimulators of the cAMP second-messenger system, as well as the cAMP analogue dibutyryl cAMP and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, did not significantly influence the GS-DNP efflux. It can be concluded that canalicular organic-anion transport in hepatocytes is either directly or indirectly regulated by PKC.
 ...
PMID:Hepatocanalicular organic-anion transport is regulated by protein kinase C. 171 82

1. In rat isolated islets of Langerhans the selective beta 2-adrenoceptor agonist, clenbuterol (1 to 20 microM), significantly increased the level of adenosine 3':5'-cyclic monophosphate (cyclic AMP) within 2 min of incubation. 2. The cyclic AMP response to clenbuterol was inhibited in the presence of the selective beta 2 adrenoceptor antagonist, ICI 118551 (0.1 or 10 microM) but remained unchanged when the beta 1-antagonist, atenolol (0.1 microM) was administered. 3. Despite causing an elevation in cyclic AMP, clenbuterol (up to 20 microM) failed to influence insulin secretion at any glucose concentration tested, even in the presence of a phosphodiesterase inhibitor. 4. By contrast, clenbuterol elicited a dose-dependent rise in the rate of glucagon secretion; the maximal agonist-induced increase in secretion was two fold, a response equivalent to that observed with 20 mM L-arginine. 5. ICI 118551 significantly inhibited the rise in glucagon secretion induced by clenbuterol (up to 20 microM). 6. The results indicate that the rat islet A cell population is equipped with functional beta 2-adrenoceptors which influence glucagon secretion via the second messenger cyclic AMP, but that the B cells are deficient in functional beta-receptors.
 ...
PMID:Selective stimulation of glucagon secretion by beta 2-adrenoceptors in isolated islets of Langerhans of the rat. 171 26

Cyclic AMP phosphodiesterase was measured in liver homogenates and microdissected periportal and perivenous liver tissue from rats in different dietary states under different conditions of substrate saturation and effector stimulation. A radiochemical microtest, more sensitive by 2-3 orders of magnitude than the usual assay, was established for the determination of the activity in liver samples corresponding to 200-800 ng dry weight. At saturating cyclic AMP concentrations (46 microM) phosphodiesterase was homogeneously distributed within the liver acinus of fed rats. Starvation for 48 h led to a decrease in the overall activity and to a heterogenous distribution with slightly higher activities in the perivenous zone. At physiological cyclic AMP concentrations (1.8 microM) phosphodiesterase showed a flat zonal gradient in livers of fed rats with higher levels in the periportal zone; after 48 h starvation it was homogeneously distributed. In the presence of cyclic GMP (2 microM) the basal activity at physiological substrate concentrations was stimulated to a greater extent in the perivenous zone. This led to a homogeneous activity distribution in the fed state and to a heterogenous pattern with a slight perivenous maximum in the fasted state. Thus there was no or only a small zonal heterogeneity of signal transmitting enzymes such as cyclic AMP phosphodiesterase and glucagon-stimulated adenylate cyclase (Zierz and Jungermann 1984). This similar signal transducing capacity in the periportal and the perivenous area will contribute to maintain the zonation of signal input due to the hormone concentration gradients across the liver acinus.
 ...
PMID:Distribution of cyclic AMP phosphodiesterase in microdissected periportal and perivenous rat liver tissue with different dietary states. 171 30

Pituitary adenylate cyclase-activating polypeptide (PACAP), a peptide of the glucagon-secretin-vasoactive intestinal polypeptide superfamily, was isolated in pure form from the brain of the European green frog, Rana ridibunda. The primary structure of the peptide indicates that evolutionary pressure to conserve the complete amino acid sequence has been very strong. Frog PACAP comprises 38 amino acid residues and contains only 1 substitution (isoleucine for valine at position 35) compared with human/ovine/rat PACAP. In the presence of the phosphodiesterase inhibitor isobutylmethylxanthine, synthetic ovine PACAP-(1-38) produced a dose-dependent increase in the concentration of cAMP in isolated frog anterior pituitary fragments (ED50 = 2.1 +/- 0.6 x 10(-7) M; mean +/- SE; n = 6). Maximum stimulation (an approximately 8-fold increase in concentration over basal values) was produced by 10(-6) M peptide. The truncated form of PACAP [PACAP-(1-27)] also produced a dose-dependent increase in cAMP in frog anterior pituitary fragments, and the potency of the peptide (ED50 = 5.9 +/- 0.6 x 10(-8) M) was comparable to that of PACAP-(1-38). The data suggest, therefore, that the function as well as the structure of PACAP have been conserved during the evolution of amphibia to mammals.
 ...
PMID:Primary structure of frog pituitary adenylate cyclase-activating polypeptide (PACAP) and effects of ovine PACAP on frog pituitary. 172 95

Autophagic degradation of cytoplasm (including protein, RNA etc.) is a non-selective bulk process, as indicated by ultrastructural evidence and by the similarity in autophagic sequestration rates of various cytosolic enzymes with different half-lives. The initial autophagic sequestration step, performed by a poorly-characterized organelle called a phagophore, is subject to feedback inhibition by purines and amino acids, the effect of the latter being potentiated by insulin and antagonized by glucagon. Epinephrine and other adrenergic agonists inhibit autophagic sequestration through a prazosin-sensitive alpha 1-adrenergic mechanism. The sequestration is also inhibited by cAMP and by protein phosphorylation as indicated by the effects of cyclic nucleotide analogues, phosphodiesterase inhibitors and okadaic acid. Asparagine specifically inhibits autophagic-lysosomal fusion without having any significant effects on autophagic sequestration, on intralysosomal degradation or on the endocytic pathway. Autophaged material that accumulates in prelysosomal vacuoles in the presence of asparagine is accessible to endocytosed enzymes, revealing the existence of an amphifunctional organelle, the amphisome. Evidence from several cell types suggests that endocytosis may be coupled to autophagy to a variable extent, and that the amphisome may play a central role as a collecting station for material destined for lysosomal degradation. Protein degradation can also take place in a 'salvage compartment' closely associated with the endoplasmic reticulum (ER). In this compartment unassembled protein chains are degraded by uncharacterized proteinases, while resident proteins return to the ER and assembled secretory and membrane proteins proceed through the Golgi apparatus. In the trans-Golgi network some proteins are proteolytically processed by Ca(2+)-dependent proteinases; furthermore, this compartment sorts proteins to lysosomes, various membrane domains, endosomes or secretory vesicles/granules. Processing of both endogenous and exogenous proteins can occur in endosomes, which may play a particularly important role in antigen processing and presentation. Proteins in endosomes or secretory compartments can either be exocytosed, or channeled to lysosomes for degradation. The switch mechanisms which decide between these options are subject to bioregulation by external agents (hormones and growth factors), and may play an important role in the control of protein uptake and secretion.
 ...
PMID:Autophagy and other vacuolar protein degradation mechanisms. 174 Jan 88

Regulation of blood glucose homeostasis is complex. Its major hormonal regulators include insulin, glucagon and somatostatin from the endocrine pancreas. Secretion of these hormones is controlled predominantly by the supply of nutrients in the circulation but also by nerve signals and other peptides. Thus, it is likely that peptides, released from cells of the gut or endocrine pancreas or from peptidergic nerves, affect glucose homeostasis by modulating the secretion of insulin, glucagon and somatostatin. When searching for novel gut peptides with such effects, diazepam binding inhibitor (DBI) was isolated from the porcine small intestine. By immunocytochemistry, DBI has been demonstrated to occur not only in the gut but also in endocrine cells of the pancreatic islets, namely in the somatostatin-producing D-cells in pig and man, and in the glucagon-producing A-cells in rat. Porcine DBI (pDBI; 10(-8)-10(-7) M) has been shown to suppress glucose-stimulated release of insulin from both isolated islets and perfused pancreas of the rat. Furthermore, secretion of insulin stimulated by either the sulfonylurea glibenclamide or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), was inhibited by the peptide. In contrast, arginine-induced release of insulin was unaffected by pDBI. Moreover, pDBI decreased arginine-induced release of glucagon from the perfused rat pancreas, whereas release of somatostatin was unchanged. Notably, rat DBI, structurally identical with rat acyl-CoA-binding protein, has also been demonstrated to inhibit glucose-stimulated release of insulin in the rat, both in vivo and in vitro. Long-term exposure of cultured fetal rat islets to pDBI (10(-8) M) significantly decreased the synthesis of DNA in islet cells.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Diazepam binding inhibitor and the endocrine pancreas. 178 37

In heart failure, an increase in the activity of the sympathetic nervous system takes place to maintain perfusion pressure to vital organs, resulting in increased levels of noradrenaline in the blood of these patients. This permanent stimulation produces a down-regulation of cardiac beta-adrenoceptors. Since noradrenaline acts primarily on the cardiac beta 1-adrenoceptor subtype, beta 1-adrenoceptors decrease in number, whereas the beta 2-adrenoceptor subpopulation remains unchanged in most instances. Consequently, the positive inotropic response to beta-adrenoceptor agonists is diminished. However, there is also a decrease in the positive inotropic effect of beta 2-adrenoceptor agonists, histamine and cAMP-phosphodiesterase inhibitors such as milrinone, whereas the positive inotropic effect of cAMP-independent Na(+)-channel activators such as DPI 206-106 and the effects of cardiac glycosides are not diminished. These observations suggest a more generalised alteration of the cAMP-adenylate cyclase system in the failing heart. Stimulatory guanine nucleotide-binding protein (Gs) couples receptors to adenylate cyclase that stimulate cAMP formation, such as beta-adrenoceptors, histamine receptors and glucagon receptors. In the failing human heart, Gs content has been reported to remain unchanged as compared with that in non-failing myocardium. However, there is a 35%-40% increase in inhibitory guanine nucleotide-binding proteins (Gi), which are involved in the receptor-mediated inhibition of adenylate cyclase. Taken together, two defects of the cAMP-adenylate cyclase system have been identified: an increase in Gi content and a decrease in the number of beta-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Alterations of the cAMP-adenylate cyclase system in the failing human heart. Consequences for the therapy with inotropic drugs]. 197 43

Glucagon exerts positive inotropic and chronotropic effects in the heart. Like its glycogenolytic effect in liver cells, the cardiac effects of glucagon are often correlated with adenylyl cyclase stimulation. Therefore, cyclic AMP-dependent phosphorylation of L-type Ca2+ channels might be involved in the inotropic effect of glucagon. There have been no reports, however, of the effects of glucagon on the cardiac Ca2+ current (ICa). Also, the physiological effects of glucagon could involve mechanisms other than stimulation of adenylyl cyclase. Here we show that glucagon enhances ICa in frog and rat ventricular myocytes. The effect of glucagon in rats resulted from a stimulation of adenylyl cyclase. In frogs, however, the effect of glucagon on ICa was smaller and occurred at a concentration tenfold lower than in rats, and adenylyl cyclase was not modified. In addition, cAMP potentiated the effect of glucagon on ICa in frog ventricle, which correlated with the observed inhibition by glucagon of low-Km cAMP phosphodiesterase activity. Therefore, this is an example of a hormone that affects cardiac function in a similar way to a variety of synthetic cardiotonic compounds, such as milrinone and Ro-20-1724. Inhibition of phosphodiesterase activity by glucagon may be essential in animals in which glucagon increases cardiac contractility but does not effectively stimulate adenylyl cyclase.
 ...
PMID:Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. 215 95

Using experimentally derived data for the activities and kinetic constants of hepatocyte cyclic AMP phosphodiesterase isoenzymes together with the derived changes in adenylate cyclase activity, due to stimulation and subsequent desensitization by glucagon, a computer model was established to simulate hepatocyte cyclic AMP metabolism. The established ability of glucagon to activate the 'dense-vesicle' cyclic AMP phosphodiesterase by eliciting its cyclic AMP-dependent phosphorylation was shown on the model to be capable of eliciting a profound reduction in the glucagon-stimulated increase in intracellular cyclic AMP. This was consistent with experimentally derived observations using the compound ICI 118233 which was used to inactivate the 'dense-vesicle' enzyme selectively. The non-hydrolysable adenosine agonist N6 (phenylisopropyl)-adenosine (PIA), which prevents glucagon pre-treatment of hepatocytes blocking the ability of insulin to stimulate the peripheral plasma membrane cyclic AMP phosphodiesterase, is shown here to accentuate the ability of insulin to decrease glucagon-elevated intracellular cyclic AMP concentrations. This effect was obliterated using the compound ICI 63197, a selective inhibitor of the peripheral plasma membrane phosphodiesterase. Computer modelling studies, taking into account experimentally derived actions in insulin in activating the peripheral plasma membrane phosphodiesterase, confirmed the potential of this enzyme to decrease intracellular cyclic AMP concentrations. Modelling of the putative effect of an insulin 'mediator' in activating the two cyclic GMP-stimulated cyclic AMP phosphodiesterase isoenzymes was shown to elicit a decrease in intracellular cyclic AMP concentrations which was comparable to that caused by insulin's action on intact hepatocytes. The relative contribution of each phosphodiesterase form to the metabolism of hepatocyte intracellular cyclic AMP, together with an assessment of the potential effect of inhibition and activation of specific species, was evaluated using the computer model. These experimental and stimulation studies indicate that alterations in the phosphodiesterase activity of the 'dense-vesicle' enzyme, the peripheral plasma membrane enzyme, the cyclic GMP-stimulated cyclic AMP isoforms and the IBMX-insensitive PDE-MQ-II can elicit profound effects upon hepatocyte intracellular cyclic AMP concentrations.
 ...
PMID:The use of selective inhibitors and computer modelling to evaluate the role of specific high affinity cyclic AMP phosphodiesterases in the hormonal regulation of hepatocyte intracellular cyclic AMP concentrations. 217 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>