Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandins, released from Kupffer cells, have been shown to mediate the increase in hepatic glycogenolysis by various stimuli such as zymosan, endotoxin, immune complexes, and anaphylotoxin C3a involving prostaglandin (PG) receptors coupled to phospholipase C via a G(0) protein. PGs also decreased glucagon-stimulated glycogenolysis in hepatocytes by a different signal chain involving PGE2 receptors coupled to adenylate cyclase via a Gi protein (EP3 receptors). The source of the prostaglandins for this latter glucagon-antagonistic action is so far unknown. This study provides evidence that Kupffer cells may be one source: in Kupffer cells, maintained in primary culture for 72 hours, glucagon (0.1 to 10 nmol/L) increased PGE2, PGF2 alpha, and PGD2 synthesis rapidly and transiently. Maximal prostaglandin concentrations were reached after 5 minutes. Glucagon (1 nmol/L) elevated the cyclic adenosine monophosphate (cAMP) and inositol triphosphate (InsP3) levels in Kupffer cells about fivefold and twofold, respectively. The increase in glycogen phosphorylase activity elicited by 1 nmol/L glucagon was about twice as large in monocultures of hepatocytes than in cocultures of hepatocytes and Kupffer cells with the same hepatocyte density. Treatment of cocultures with 500 mumol/L acetylsalicylic acid (ASA) to irreversibly inhibit cyclooxygenase (PGH-synthase) 30 minutes before addition of glucagon abolished this difference. These data support the hypothesis that PGs produced by Kupffer cells in response to glucagon might participate in a feedback loop inhibiting glucagon-stimulated glycogenolysis in hepatocytes.
...
PMID:Feedback-inhibition of glucagon-stimulated glycogenolysis in hepatocyte/Kupffer cell cocultures by glucagon-elicited prostaglandin production in Kupffer cells. 759 Jun 78

An immortalized cell line, called P9, was derived from hepatocytes by transfection with SV40 DNA. These cells expressed enzyme activities characteristic of hepatocytes, namely glucose-6-phosphatase, glycogen phosphorylase, bilirubin glucuronyltransferase and both glucagon- and prostaglandin E1 (PGE1)-stimulated adenylate cyclase activities, albeit at decreased levels compared with native hepatocytes. Levels of the G-protein subunits alpha-Gi-2, alpha-Gi-3, G beta and the 'long' form of alpha-G2 (45 kDa) were approximately 4-fold higher relative to native hepatocytes, whereas those of the 'short' form of alpha-G2 (42 kDa) were lower by approximately 40%. Associated with this were marked alterations in the guanine nucleotide regulation of adenylate cyclase. Receptor-mediated stimulation, achieved by either PGE1 or glucagon, was apparent in P9 cells, although the latter was only evident upon amplification with forskolin. Glucagon-stimulated cyclic AMP accumulation in P9 cells did not exhibit desensitization, as in hepatocytes, nor was the phosphorylation of alpha-Gi-2 evident. Culture of P9 cells with insulin led to a dose-dependent decrease (EC50 0.2 +/- 0.1 nM) in the ability of PGE1 to stimulate adenylate cyclase activity, with the maximum effect attained after approximately 6 h. A comparable attenuation of stimulation was seen for glucagon- and guanine-nucleotide-stimulated adenylate cyclase activities. In cells cultured with insulin, lower levels of GTP were required to stimulate adenylate cyclase, ADP-ribosylation of the 45 kDa form of alpha-Gs with cholera toxin was attenuated, and the expression of both alpha Gi-2 and alpha-Gi-3 was increased. It is suggested that the expression of alpha-Gi-2 and alpha-Gi-3 may be directly regulated by the action of insulin in hepatocytes and P9 cells.
...
PMID:Analysis of the adenylate cyclase signalling system, and alterations induced by culture with insulin, in a novel SV40-DNA-immortalized hepatocyte cell line (P9 cells). 801 Sep 67

Lithium is thought to have an insulin-like effect on glucose transport and metabolism in skeletal muscle and adipocytes. However, we found that lithium had only a minimal effect on basal glucose transport activity in rat epitrochlearis muscles. Instead, lithium markedly increased the sensitivity of glucose transport to insulin, so that the increase in glucose transport activity induced by 300 pM insulin was approximately 2.5-fold greater in the presence of lithium than in its absence. Lithium also caused a modest increase in insulin responsiveness. This enhancement of the susceptibility of the glucose transport process to stimulation was not limited to insulin, because lithium induced increases in the susceptibility of glucose transport to stimulation by contractile activity, hypoxia, a phorbol ester, and phospholipase C. Lithium also blunted the activation of glycogen phosphorylase by epinephrine. These effects were not mediated by inhibition of adenylate cyclase, because neither basal- nor epinephrine-stimulated muscle cAMP concentration was affected by lithium treatment. The effects of lithium on glucose transport and metabolism in skeletal muscle are strikingly similar to the persistent effects of exercise. These results support the possibility that lithium might be useful in the treatment of insulin resistance in patients with non-insulin-dependent diabetes mellitus.
...
PMID:Lithium increases susceptibility of muscle glucose transport to stimulation by various agents. 801 55

Adenylate cyclase, the catalytic protein that converts ATP to cAMP, plays a fundamental role in adrenergic signal transduction. Adenylate cyclase activity (pmol cAMP/mg/min) is generally assayed by measuring radiolabeled cAMP generated from [alpha-32P]ATP. Although sensitive, the radioactive approach is costly and time consuming. Given safety and environmental concerns, we developed a highly sensitive fluorometric assay for adenylate cyclase activity. This assay depends upon the breakdown of cAMP by phosphodiesterase to AMP, and the subsequent stimulation by AMP of glycogen phosphorylase a. Radioactive and fluorescence methods were compared using the same ventricular membrane preparations from five different rabbit hearts. Theophylline, used in the fluorometric assay, increased basal adenylate cyclase activity. However, adenylate cyclase kinetics, the dose response to isoproterenol, and the "fold" stimulation (agonist stimulated/basal adenylate cyclase activity) after isoproterenol (10(-6)M), guanylyl-5'-imidodiphosphate (GppNHp) (10(-4)M), and NaF (10(-2)M) were nearly identical with both methods. Adenylate cyclase activity can be measured with the fluorometric assay in samples as small as 10 micrograms of membrane protein. In summary, this new fluorometric assay is highly sensitive, safer, less costly, and less time consuming than radioactive assays for adenylate cyclase activity.
...
PMID:An enzymatic fluorometric assay for adenylate cyclase activity. 838 28

1. ATP exerts multiple receptor-mediated effects on isolated hepatocytes: glycogenolysis through the activation of glycogen phosphorylase (cAMP-independent, IP3/calcium-mediated), inactivation of glycogen synthase, inhibition of the glucagon effect on cAMP, activation of phospholipase D. The fact that some of these effects can be selectively altered and that they are not, or differently, reproduced by some other analogues of ATP, suggests the presence of more than one receptor. (i) Pertussis toxin abolishes the anti-glucagon effect of ATP without affecting its glycogenolytic effect. (ii) Single cell calcium measurements reveal major differences between ATP and ADP, (iii) 2MeSATP and ADP beta S, in clear contrast to ATP, barely increase the levels of IP3 and their glycogenolytic effects is completely blocked by phorbol ester treatment of hepatocytes. (iv) 2MeSATP differs from ADP beta S since it has no anti-glucagon effect. 2. Effects of UTP on isolated hepatocytes so far do not show any difference with effects of ATP, suggesting interaction with the same receptor(s). 3. It is proposed that liver plasma membranes contain (at least) three different receptors mediating (a) the activation of phospholipase C, (b) the activation of phospholipase D and (c) the inhibition of adenylate cyclase.
...
PMID:The complex interaction of ATP and UTP with isolated hepatocytes. How many receptors? 848 12

As demonstrated previously, liver acini draining the blood from intraportally transplanted pancreatic islets in streptozotocin-diabetic rats are altered in various respects. The hepatocytes in these acini store glycogen and/or fat, and they show an increase in proliferation as well as in apoptotic activity. Thus, they are phenotypically similar to carcinogen-induced preneoplastic liver foci (glycogen-storing foci and sometimes also mixed cell foci). By means of catalytic enzyme histochemistry or immunohistochemistry, we investigated the activity of key enzymes of alternative pathways of carbohydrate metabolism and some additional marker enzymes (well known from studies on preneoplastic hepatic foci) in the altered liver acini surrounding the islet isografts. In addition, the expression of glucose transporter proteins 1 and 2 (GLUT-1 and GLUT-2) were investigated immunohistochemically. The activities of hexokinase, pyruvate kinase, glyceraldehyde-3-phosphate dehydrogenase, and glucose-6-phosphate dehydrogenase were increased, whereas the activities of glycogen phosphorylase, adenylate cyclase, glucose-6-phosphatase, and membrane-bound adenosine triphosphatase were decreased in the altered liver acini. The expression of GLUT-2 was also decreased. GLUT-1 and glutathione S-transferase placental form were not expressed, and the activities of glycogen synthase and gamma-glutamyl-transferase remained unchanged. All changes of the enzyme activities were in line with the well known effects of insulin and resembled alterations characteristic of preneoplastic liver foci observed in different models of hepatocarcinogenesis. It remains to be clarified in long-term experiments whether or not these foci represent preneoplastic lesions and may proceed to neoplasia.
...
PMID:Altered liver acini induced in diabetic rats by portal vein islet isografts resemble preneoplastic hepatic foci in their enzymic pattern. 864 65

[des-His1, des-Phe6,Glu9]Glucagon-NH2 is a newly designed glucagon antagonist. This analog has a binding IC50 of 48 nM (compared to glucagon IC50 of 1.5 nM) and demonstrates pure antagonism in an adenylate cyclase assay. Although the number of glucagon antagonists has grown rapidly recently, closer examination suggested that many of these antagonists retained very low, almost imperceptible levels of cAMP accumulation that were sufficient to elicit an in vivo biological response. To investigate more carefully this secondary biological signal, we measured cAMP accumulation in a revised assay using isolated hepatocytes in the presence of the phosphodiesterase (PDE) inhibitor Rolipram. The PDE inhibitors Rolipram and isobutyl-1-methylxanthine (IBMX) increased the sensitivity of the cAMP accumulation assay from approximately 10-fold for the native hormone to 35-fold above basal levels. On the other hand, amrinone, another PDE inhibitor, did not affect the cAMP accumulation caused by glucagon. The use of PDE inhibitors indicated that three glucagon analogs that had previously been reported to have strong antagonist properties in classical adenylate cyclase assays were actually weak partial agonists in this new assay system. [N alpha-Trinitrophenyl-His1, homo-Arg12]glucagon, [des-amino-His1,D-Phe4,Tyr5, Arg12, Lys17,18,Glu21]glucagon, and [des-His1,Glu9]glucagon-NH2 demonstrated 233%, 21%, and 5.5% cAMP accumulation relative to the native hormone in the presence of 25 microM Rolipram. On the other hand, [des-His1,des-Phe6,Glu9]glucagon-NH2, a newly designed glucagon antagonist, did not activate adenylate cyclase in the presence of Rolipram up to a maximal physiological concentration of 1 microM, indicating that it was a pure antagonist of glucagon-induced adenylate cyclase activity and also the first one in this class. This compound and others were tested in a glycogen phosphorylase assay. As [des-His1,des- Phe6,Glu9]glucagon-NH2 did not activate phosphorylase activity, it was chosen as our candidate for in vivo testing in streptozotocin-induced diabetic rats. An initial dose of 0.75 mg/kg was found to cause the greatest lowering of blood glucose levels (to 63% of the initial levels in 15 min) when the bolus was followed by continuous infusion of 25 micrograms/kgxmin for 1 h.
...
PMID:Low level cyclic adenosine 3',5'-monophosphate accumulation analysis of [des-His1, des- Phe6, Glu9] glucagon-NH2 identifies glucagon antagonists from weak partial agonists/antagonists. 875 57

Classification is central to many studies of protein structure, function, and evolution. This article presents a strategy for classifying protein three-dimensional structures. Methods for and issues related to secondary structure, domain, and class assignment are discussed, in addition to methods for the comparison of protein three-dimensional structures. Strategies for assigning protein domains to particular folds and homologous superfamilies are then described in the context of the currently available classification schemes. Two examples (adenylate cyclase/DNA polymerase and glycogen phosphorylase/beta-glucosyltransferase) are presented to illustrate problems associated with protein classification.
...
PMID:Classification of protein folds. 1187 96

Neuropeptides of the adipokinetic hormone (AKH) family regulate inter alia mobilisation of various substrates from stores in the fat body of insects during episodes of flight. How is this achieved? In insects which exclusively oxidise carbohydrates for flight (cockroaches), or which oxidise carbohydrates in conjunction with lipids (locusts) or proline (a number of beetles), the endogenous AKHs bind to a G(q)-protein-coupled receptor, activate a phospholipase C and the resulting inositol trisphosphate releases Ca(2+) from internal stores. In addition, influx of extracellular Ca(2+) is increased and, via a kinase cascade, glycogen phosphorylase is activated, glucose-1-phosphate produced, and transformed to trehalose, which is released into the haemolymph. In locusts, additionally, adenylate cyclase is activated and cyclic AMP is synthesised. In insects which use lipids for sustained flight (locust, tobacco hornworm moth) or proline for flight (certain beetles), adenylate cyclase is activated after the AKHs bind to their respective G(s)-protein-coupled receptor. The resulting cyclic AMP, together with the messengers intra- and extracellular Ca(2+), activate a triacylglycerol lipase, which results in the production of 1,2 diacylglycerols (in locusts, moths) or (hypothetically) free fatty acids (fruit beetle).
...
PMID:Mode of action of neuropeptides from the adipokinetic hormone family. 1276 39

Although the enzymes enabling Hypocrea jecorina (anamorph Trichoderma reesei) to degrade the insoluble substrate cellulose have been investigated in some detail, little is still known about the mechanism by which cellulose signals its presence to the fungus. In order to investigate the possible role of a G-protein/cyclic AMP signaling pathway, the gene encoding GNA3, which belongs to the adenylate cyclase-activating class III of G-alpha subunits, was cloned. gna3 is clustered in tandem with the mitogen-activated protein kinase gene tmk3 and the glycogen phosphorylase gene gph1. The gna3 transcript is upregulated in the presence of light and is almost absent in the dark. A strain bearing a constitutively activated version of GNA3 (gna3QL) exhibits strongly increased cellulase transcription in the presence of the inducer cellulose and in the presence of light, whereas a gna3 antisense strain showed delayed cellulase transcription under this condition. However, the gna3QL mutant strain was unable to form cellulases in the absence of cellulose. The necessity of light for stimulation of cellulase transcription by GNA3 could not be overcome in a mutant which expressed gna3 under control of the constitutive gpd1 promoter also in darkness. We conclude that the previously reported stimulation of cellulase gene transcription by light, but not the direct transmission of the cellulose signal, involves the function and activation of GNA3. The upregulation of gna3 by light is influenced by the light modulator ENVOY, but GNA3 itself has no effect on transcription of the light regulator genes blr1, blr2, and env1. Our data for the first time imply an involvement of a G-alpha subunit in a light-dependent signaling event in fungi.
...
PMID:The G-alpha protein GNA3 of Hypocrea jecorina (Anamorph Trichoderma reesei) regulates cellulase gene expression in the presence of light. 1913 72


<< Previous 1 2 3 4

---