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)

A hypersensitivity of glycogen phosphorylase activation by epinephrine and glucagon has been demonstrated in isolated perfused working and non-working hearts from diabetic rats. Accumulation of tissue cAMP and activation of cAMP-dependent protein kinase in response to epinephrine and glucagon were no greater and usually less in hearts of diabetic than of normal rats. Insulin deficiency was not associated with greater changes in epinephrine-induced activation of glycogen phosphorylase kinase than that observed in normal hearts. Perfusion of hearts with subphysiological concentrations of calcium (0.83 mM) partially reversed the diabetes-related hypersensitivity of phosphorylase activation by epinephrine. The phosphorylase activation hypersensitivity to epinephrine was completely reversed by adrenalectomizing diabetic rats 5 days before heart perfusion, an effect potentially caused by steroid-induced changes in cardiac calcium metabolism. These data are consistent with the hypothesis that phosphorylase activation by phosphorylase kinase is allosterically increased in the diabetic due to a diabetes-related increase in free intracellular calcium concentrations.
 ...
PMID:Phosphorylase activation hypersensitivity in hearts of diabetic rats. 632 Jun 71

The ability of the Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate (Rp cAMPS) to inhibit glucagon-induced glycogenolysis was studied in hepatocytes isolated from fed rats. Preincubation of the cells for 20 min with progressively higher concentrations of Rp cAMPS followed by a 1 X 10(-9) M glucagon challenge resulted in a 50% inhibition of glucose production over a 30-min period at 2-3 X 10(-6) M Rp cAMPS. A maximal inhibition of 50-74% was achieved, the actual value depending upon the length of preincubation with Rp cAMPS. The inhibitory effect did not increase when the concentration of Rp cAMPS was increased from 3 X 10(-6) to 3 X 10(-4) M. Addition of 1 X 10(-5) M Rp cAMPS to the cells followed by 10(-11) to 10(-6) M glucagon shifted the glucagon concentration required for half-maximal glucose production measured at 10 min to 6-fold higher glucagon concentrations and the concentration of glucagon required for apparent maximal glucose production measured at 10 min to greater than 10-fold higher glucagon concentrations. The cAMP-dependent protein kinase activation curve was similarly shifted to higher concentrations of glucagon. These data show that Rp cAMPS acts as a cAMP antagonist capable of opposing the glucagon-induced activation of cAMP-dependent protein kinase and the concomitant activation of the glycogenolytic cascade.
 ...
PMID:Inhibition of glucagon-induced glycogenolysis in isolated rat hepatocytes by the Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate. 633 Jan 2

Glucagon caused a marked decrease in the total L-pyruvate kinase activity of control hepatocytes maintained in monolayer culture (t1/2 = 54 h), while the addition of insulin to hepatocytes isolated from a fasted rat caused a four- to fivefold increase in the total enzyme activity. Maintenance of L-pyruvate kinase in control cultures of hepatocytes was shown to require insulin. However, when 1 microM glucagon was present in the medium, the total L-pyruvate kinase activity was not maintained even in the presence of 1 microM insulin, but rather the total L-pyruvate kinase activity of the cells steadily declined from 12.1 to 5.7 units/mg DNA by the 6th day in culture. The increase in the total L-pyruvate kinase activity of fasted hepatocytes cultured in the presence of insulin was shown to result from an increase in protein synthesis, since actinomycin D and cycloheximide blocked the insulin-induced increase in the enzyme activity. The addition of 1 microM glucagon to cultures of fasted hepatocytes also blocked the insulin-induced increase in total L-pyruvate kinase activity. Since glucagon decreased the total L-pyruvate kinase activity in control hepatocytes and blocked the increase in L-pyruvate kinase activity in fasted hepatocytes, it is suggested that, in addition to the phosphorylation of L-pyruvate kinase by a cAMP-dependent protein kinase, glucagon also acts to decrease the synthesis of L-pyruvate kinase in vitro.
 ...
PMID:The long-term effect of glucagon on pyruvate kinase activity in primary cultures of hepatocytes. 638 58

We describe here an activable neutral cholesteryl esterase (EC 3.1.1.13) in arteries similar to the hormone-sensitive lipase of adipose tissue and adrenal cortex. Maximum enzyme activity in rabbit aorta was given by cholesteryl ester substrates dispersed as a mixed micelle with phosphatidylcholine and Na taurocholate (molar ratio 1:4:2). A quantitative assay of enzymic activity was obtained with the following component concentrations: 6.0 microM cholesteryl [1-14C]oleate, 23.7 microM phosphatidylcholine, 12.5 microM Na taurocholate, 0.04% serum albumin, and 85 mM K phosphate buffer, pH 7.0. The enzymic activity in aortic homogenates was stimulated 2-fold by addition of 5 microM glucagon or 100 microM dibutyryl cAMP. This activation was Mg-ATP dependent. Addition of 50 micrograms/ml of exogenous protein kinase could reverse the action of protein kinase inhibitor on dibutyryl cAMP activation of the neutral cholesteryl esterase. In addition to activation by cAMP-dependent protein kinase, the enzyme could be distinguished from the more active arterial lysosomal cholesteryl esterase by its pH 7.0 optimum, relative stability to preincubation at elevated temperatures, and exclusive localization in the cell cytosol. Subcellular fractionation of lipid-laden arterial foam cells revealed a significant portion of the neutral cholesteryl esterase bound to cytoplasmic cholesteryl ester-rich lipid droplets. Our results suggest that the breakdown of cytoplasmic cholesteryl ester droplets in arterial cells may be under hormonal regulation.
 ...
PMID:Arterial neutral cholesteryl esterase. A hormone-sensitive enzyme distinct from lysosomal cholesteryl esterase. 684 93

cAMP has neutrotrophic effects in the nervous system. We have investigated whether there is a correlation between cAMP-induced neurite outgrowth and induction of chromogranin B and synapsin I gene expression. These genes encode marker proteins of distinct populations of vesicles in neurons, neuroendocrine and endocrine cells, and in addition, they contain a cAMP response element (CRE) in their upstream regions, making it likely that cAMP-induced neuronal differentiation might be accompanied by increased transcription of these genes. We increased intracellular cAMP levels in neuronal and neuroendocrine cells and analyzed the levels of chromogranin B and synapsin I mRNA. Our data revealed that, while chromogranin B mRNA was in fact induced following cAMP stimulation, synapsin I mRNA was not affected. To analyze the cis-acting sequences, we constructed hybrid genes containing the upstream region of the mouse chromogranin B gene fused to a reporter gene. Similar plasmids containing the synapsin I or the glucagon promoter were constructed. Transfections of neuronal and endocrine cells, together with deletion mutagenesis, revealed that the CRE of the chromogranin B gene mediated the effect of cAMP upon transcription. This effect was mimicked by overexpression of the catalytic subunit of the cAMP-dependent protein kinase. In addition, overexpression of the negative-acting CRE-binding protein CREB-2 revealed that the chromogranin B CRE functions as a bifunctional genetic regulatory element in that it mediates basal as well as cAMP-stimulated transcription. Synapsin I gene expression, however, was not induced by either elevated intracellular cAMP concentration or by overexpression of protein kinase A, although a similar pattern of proteins, including CREB, bound to the synapsin I and chromogranin B CRE in vitro. Thus while the CRE element in the chromogranin B gene promoter is responsive to cAMP, the same element, when present in the synapsin I promoter, does not confer cAMP inducibility.
 ...
PMID:Differential regulation of chromogranin B and synapsin I gene promoter activity by cAMP and cAMP-dependent protein kinase. 752 78

Type III adenylyl cyclase is stimulated by beta-adrenergic agonists and glucagon in vitro and in vivo, but not by Ca2+ and calmodulin. However, the enzyme is stimulated by Ca2+ and calmodulin in vitro when it is concomitantly activated by the guanyl nucleotide stimulatory protein Gs (Choi, E. J., Xia, Z., and Storm, D. R. (1992a) Biochemistry 31, 6492-6498). Here, we examined regulation of type III adenylyl cyclase by Gs-coupled receptors and intracellular Ca2+ in vivo. Surprisingly, intracellular Ca2+ inhibited hormone-stimulated type III adenylyl cyclase activity. Submicromolar concentrations of intracellular free Ca2+, which stimulated type I adenylyl cyclase, inhibited glucagon- or isoproterenol-stimulated type III adenylyl cyclase. Inhibition of type III adenylyl cyclase by intracellular Ca2+ was not mediated by Gi, cAMP-dependent protein kinase, or protein kinase C. However, an inhibitor of CaM kinases antagonized Ca2+ inhibition of the enzyme, and coexpression of constitutively activated CaM kinase II completely inhibited isoproterenol-stimulated type III adenylyl cyclase activity. We propose that Ca2+ inhibition of type III adenylyl cyclase may serve as a regulatory mechanism to attenuate hormone-stimulated cAMP levels in some tissues.
 ...
PMID:Ca2+ inhibition of type III adenylyl cyclase in vivo. 766 59

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.
 ...
PMID:Increasing cAMP attenuates activation of mitogen-activated protein kinase. 769 90

The involvement of adenosine 3',5'-cyclic monophosphate (cAMP) in the stimulation of ventricular protein synthesis by aortic hypertension or adrenergic agonists in the adult rat heart was investigated. In either the retrogradely or anterogradely perfused heart, aortic hypertension increased protein synthesis rates by up to 19%. However, no changes in cAMP concentrations or in cAMP-dependent protein kinase activity ratios could be detected either at early (< 5 min) or late (90 min) time points. Although isoproterenol, 3-isobutyl-1-methylxanthine, or forskolin raised cAMP concentrations (by up to 4.5-fold) and cAMP-dependent protein kinase ratios (by up to 4-fold), protein synthesis rates were not increased; however, under some perfusion conditions, glucagon did stimulate protein synthesis by 25%. Epinephrine stimulated protein synthesis by up to 32%, an effect that was not prevented by propranolol. Phenylephrine also stimulated protein synthesis, an effect that was prevented by prazosin but was unaffected by yohimbine. These findings implicate the alpha 1-adrenoceptor in the regulation of cardiac protein synthesis. Because changes in adenine nucleotide concentrations were similar in hearts perfused with epinephrine or with the agents that raised cAMP, it is unlikely that adenine nucleotide depletion is responsible for the failure to observe effects of the latter group of agents on protein synthesis. Although isoproterenol or forskolin raised cAMP concentrations in isolated ventricular cardiomyocytes where ATP depletion was minimal, neither stimulated protein synthesis. alpha 1-Adrenergic agonists stimulate phosphoinositide hydrolysis in the heart (Brown, J. H., I. L. Buxton, and L. L. Brunton. Circ. Res. 57:532-537, 1985). Aortic hypertension doubled the rate of phosphoinositide hydrolysis in the perfused heart. We suggest that the phosphoinositide-linked signal transduction pathway is more likely to be involved in stimulation of cardiac protein synthesis by hypertension or adrenergic agonism than the adenylyl cyclase/cAMP-linked pathway.
 ...
PMID:cAMP and protein synthesis in isolated adult rat heart preparations. 769 91

Glucagon decreases glutathione synthesis in hepatocytes from well-nourished rats. However, in hepatocytes from malnourished rats, glucagon does not inhibit glutathione synthesis, suggesting a desensitization of cAMP-mediated signal transduction. We investigated the mechanism for this desensitization of cAMP-mediated responsiveness in malnourished rats by comparing the signal transduction pathways in rats fed very low protein diets (0.5 g protein/100 g diet) with those of rats fed diets adequate in protein (15 g protein/100 g diet) for 2 wk. Glucagon receptor and forskolin-stimulated cAMP production were greater in hepatocytes from malnourished rats. Stimulation of adenylyl cyclase with forskolin, guanine nucleotides or manganese in hepatic membranes was also enhanced after malnutrition. Moreover, quantity of the stimulatory guanine nucleotide regulatory protein was 70-80% greater in hepatocytes from malnourished rats but the inhibitory guanine nucleotide regulatory protein was not different. These results suggested that desensitization of cAMP-mediated signal transduction after malnutrition occurred at a site distal to cAMP production. Maximal activity of cAMP-dependent protein kinase was 60% lower in liver homogenates from malnourished rats compared with controls. This difference in activity was confined to the cytosolic compartment, with no difference in activity observed in the particulate fraction. Lower activity of cAMP-dependent protein kinase in the cytosol of malnourished rats was associated with a 43% reduction in the quantity of regulatory subunit type I, with no difference in the regulatory subunit type II. These data indicate that desensitization of cAMP signal transduction in rat liver after malnutrition is due to a decrease in the quantity and activity of cAMP-dependent protein kinase.
 ...
PMID:Activity of cAMP-dependent protein kinase is reduced in protein-energy malnourished rats. 787 14

The effects of glucagon on serine: pyruvate/alanine: glyoxylate aminotransferase (SPT/AGT) gene expression were studied in primary cultured rat hepatocytes. When hepatocytes had been precultured for 16-18 h under serum- and hormone-free conditions, the addition of glucagon caused (after a lag period of about 2 h) a remarkable increase in the cellular level of SPT/AGT mRNA by 4 h in a time- and dose-dependent manner. The induced mRNA was that for mitochondrial SPT/AGT, as judged by ribonuclease protection analysis. A nuclear run-on assay revealed that activation of transcription is responsible for the increase in mitochondrial SPT/AGT mRNA and that the maximal rate of transcription occurs 1.5 h after glucagon addition. The effect of glucagon was mimicked by 8-bromo-cAMP and suppressed by N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide, an inhibitor of cAMP-dependent protein kinase (protein kinase A), while both 12-O-tetradecanoylphorbol-13-acetate and A23187 were without effect in elevating the SPT/AGT mRNA level, suggesting that the cAMP/protein kinase A system is involved in the regulation of SPT/AGT gene expression. In hepatocytes precultured for 16-18 h under serum- and hormone-free conditions, the glucagon-induced transcription was severely inhibited by cycloheximide. When the preculture was for 2 h, on the other hand, the activation of transcription by glucagon was more rapid, and the inhibition by cycloheximide was less than that observed with cells precultured for 16-18 h, suggesting that a short-lived protein factor is involved in the hormonal regulation. The glucagon-induced expression of the SPT/AGT gene was also turned off by dexamethasone.
 ...
PMID:Regulation by glucagon of serine: pyruvate/alanine: glyoxylate aminotransferase gene expression in cultured rat hepatocytes. 813 20


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