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At least 1,261 records · Page 70Linked to original sources
PubMed1996

Lysophosphatidic acid-induced neurite retraction in PC12 cells: neurite-protective effects of cyclic AMP signaling.

Effects of the cyclic AMP second messenger system were studied on the retraction of neurites elicited by the phospholipid mediator lysophosphatidic acid (LPA) in PC12 cells. LPA stimulation inhibited adenylyl cyclase, indicating that the LPA receptor couples to the heterotrimeric Gi proteins. However, pertussis toxin or expression of dominant negative Ras did not prevent neurite retraction. In contrast, cholera toxin, forskolin, and application of dibutyryl-cyclic AMP prevented neurite retraction. The neurite-protective effect of forskolin was blocked by Rp-adenosine 3',5'-phosphorothioate. Forskolin and dibutyryl-cyclic AMP both failed to protect neurites in A126-1B2 and 123.7 cells, which lack cyclic AMP-activated protein kinase. Data indicate that elevation of cyclic AMP levels triggers a cyclic AMP-activated protein kinase-dependent mechanism that opposes the functioning of the morphoregulatory signaling activated by LPA. ADP-ribosylation of Rho by the Clostridium botulinum C-3 toxin in 123.7 cells caused neuronal differentiation, indicated by neurite extension, and blocked LPA-induced neurite retraction. LPA activates Gq- and Gi-linked signaling in parallel; therefore, a morphoregulatory signaling network hypothesis is proposed versus the simplistic approach of a signaling pathway. The signaling network integrates the receptor-activated individual, sequential, and parallel signaling events into an interactive network whose individual components may fulfill required and permissive functions encoding the cellular response.

ADP Ribose Transferases↗
PubMed2005

Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491.

Previous studies showed that insulin antagonizes AMP-activated protein kinase activation by ischemia and that protein kinase B might be implicated. Here we investigated whether the direct phosphorylation of AMP-activated protein kinase by protein kinase B might participate in this effect. Protein kinase B phosphorylated recombinant bacterially expressed AMP-activated protein kinase heterotrimers at Ser(485) of the alpha1-subunits. In perfused rat hearts, phosphorylation of the alpha1/alpha2 AMP-activated protein kinase subunits on Ser(485)/Ser(491) was increased by insulin and insulin pretreatment decreased the phosphorylation of the alpha-subunits at Thr(172) in a subsequent ischemic episode. It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser(485)/Ser(491) phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr(172) by LKB1 and the resulting activation of AMP-activated protein kinase.

AMP-Activated Protein Kinase Kinases↗
PubMed1990

Genetically determined alcohol preference and cyclic AMP binding proteins in mouse brain.

Free-choice consumption of alcohol by mice with differing phenotypic alcohol preferences caused uniformly large decreases in brain cyclic AMP-dependent protein kinase activity toward an exogenous substrate (histone 2b) but the effect of alcohol on brain cyclic AMP binding activity was strain-specific. Furthermore, particulate kinase phosphorylating activity toward an endogenous protein (kinase regulatory subunit, RII) was altered by alcohol consumption in a strain-specific manner. The changes in cyclic AMP binding and phosphorylating activity appeared to result from phenotypic differences in the brain's response to alcohol. Thus, low preference animals were sensitive to alcohol and showed a large decrease in cyclic AMP binding and an increase in phosphorylation of regulatory subunit in response to alcohol. In contrast, high preference strain had only a small decrease in cyclic AMP binding and a decrease in phosphorylation, even though these animals consumed a significantly larger dose of alcohol. These data suggest that changes in cyclic AMP binding and/or phosphorylation of kinase regulatory subunit may be phenotypic markers of alcohol preference in inbred mice.

Alcoholism↗
PubMed1983

Cyclic AMP phosphodiesterase activity in rat brain following chronic treatment with lithium, imipramine, reserpine, and combinations of lithium with imipramine or reserpine.

The adaptability of the cyclic AMP phosphodiesterase (PDE) following chronic treatment (4-6 weeks) with lithium, reserpine, imipramine, and combinations of lithium with imipramine or reserpine has been studied in rat brain tissue. All drugs, except lithium, were given intraperitoneally once a day. Control animals received only vehicle. Lithium was given in the diet in a concentration yielding a plasma level of 0.5-0.6 mmol/l. The PDE activity was measured in homogenates from cerebral cortex and "limbic" forebrain. These two brain areas were both found to contain three types of PDE activity. One was mainly associated with the pellet after a 10,000 X g centrifugation for 10 min. This enzyme hydrolyzed both cyclic AMP and cyclic GMP with a Km value of 130 +/- 48 microM for cyclic AMP, but was insensitive to calcium and calmodulin. Two types were mainly found in the supernatant after the centrifugation with Km values cyclic AMP of 300 +/- 108 microM and 4 +/- 3 microM, respectively. The former hydrolyzed both cyclic AMP and cyclic GMP and was stimulated 7-fold by calcium and calmodulin, while the latter only hydrolyzed cyclic AMP and was insensitive to calcium and calmodulin. None of the treatments affected the "pellet" enzyme or the low affinity enzyme from the supernatant. However, lithium treatment, even combined with reserpine or imipramine, increased the high affinity enzyme. This increase was also apparent in the DEAE-ion exchange chromatographic profile of the PDE enzymes.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Interrelated calcium ion and cyclic AMP inhibition of placental lactogen secretion by cultured human term trophoblast.

Calcium ion has been shown to have a negative regulatory effect on the secretion of human placental lactogen (hPL). We report an inhibitory effect of cyclic AMP on hPL secretion in a model system of cultured human term trophoblast. Similar results were obtained by modulation of cyclic AMP-phosphodiesterase. The effects of ionophore A23187 and cyclic AMP were non-additive. In searching for the sequence of the common pathway, we found that the ionophore A23187 reduced cyclic AMP concentration and that the inhibitory effect of cyclic AMP was abolished by verapamil, a calcium channel blocker, and by trifluoperazine, a calcium-calmodulin inhibitor. Cyclic AMP seems to mobilize intracellular calcium, and the latter, by way of a calcium-calmodulin complex, modulates the secretion of hPL.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1981

Cyclic AMP concentrations in plasma, cerebrospinal fluid and urine in patients with acute cerebral hemispheric infarction.

Plasmas, cerebrospinal fluid and urine were sampled from 22 patients with cerebral hemispheric infarction and analyzed for cyclic AMP. The following observations were made: (1) In mild cases with slight dysarthria and/or hemiparesis but without disturbance of consciousness (Group I), cyclic AMP in peripheral venous plasma (PVP) remained over the normal lowest level more than 10 days after the onset. Patients with apparent neurological deficits could be divided into two groups. In one group, cyclic AMP in PVP decreased to a subnormal level within about 5 days after the onset of stroke (Group II). In another group (Group III), such a decrease was not observed. Brain isotope scintigrams were revealed negative in Group I. The size of brain infarct as judged by isotope uptake was larger in Group III than in Group II, except for a few cases in which the lesion was restricted in the basal ganglionic region. (2) No clinical significance was, however, found in the time course of cyclic AMP levels in internal jugular venous or femoral arterial plasma, or in cerebrospinal fluid, or of the daily amount of cyclic AMP excretion into urine. (3) Cerebral arterio-venous difference of cyclic AMP was negative in most of the cases.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

Serotonin N-acetyltransferase mRNA levels in photoreceptor-enriched chicken retinal cell cultures: elevation by cyclic AMP.

Serotonin N-acetyltransferase (AA-NAT; arylalkylamine N-acetyltransferase; EC 2.3.1.87) is a key regulatory enzyme in the biosynthesis of melatonin. Previous studies have shown that the activity of this enzyme in the chicken retina is regulated by a cyclic AMP-dependent mechanism. In the present report, we investigated whether cyclic AMP can regulate the levels of AA-NAT mRNA in photoreceptor-enriched chick retinal cell cultures. AA-NAT mRNA levels were elevated by acute treatment with cyclic AMP protagonists, including forskolin; this response was blocked by H-89, a selective inhibitor of cyclic AMP-dependent protein kinase. Forskolin did not alter the rate of disappearance of AA-NAT mRNA in actinomycin D-treated cells, suggesting that cyclic AMP enhances transcription of the AA-NAT gene. Forskolin-induced elevation of AA-NAT mRNA levels was enhanced by cycloheximide, which decreased the degradation of the transcript in cells treated with actinomycin D. These studies indicate that the abundance of AA-NAT mRNA is regulated in part through a cyclic AMP-dependent mechanism.

Animals↗
PubMed1985

Export of cyclic AMP from avian red cells. Independence from major membrane transporters and specific inhibition by prostaglandin A.

Prostaglandin A1 (PGA1) inhibits energy-dependent cyclic AMP export by pigeon red cells [Brunton and Mayer, J. Biol. Chem. 254:9714 (1979)]. To assess the specificity of this action, we observed the effect of 10 microM PGA1 (a concentration that inhibits cyclic AMP efflux greater than 95%) on a variety of membrane-protein-mediated processes that we could readily characterize and quantify in the pigeon red cell. Included in this study were isoproterenol-sensitive cyclic AMP production, ouabain-inhibitable 86Rb+ influx, furosemide-sensitive NaCl-KCl symport, 4-acetamido-4'-isothiocyano-2, 2'-disulfonic stilbene (SITS)-sensitive sulfate exchange, Na+-dependent alpha-aminoisobutyrate influx, and glucose and adenosine uptake. Remarkably, none of these membrane activities is significantly affected by PGA1. Furthermore, SITS, nitrobenzylthioinosine, cytochalasin B, and Na+-free extracellular medium (inhibitors of band 3, the nucleoside transporter, the hexose transporter, and amino acid uptake, respectively), failed to inhibit cyclic AMP export by pigeon red cells. On the basis of this data, we conclude that PGA1 does not act via a generalized alteration of a basic property at the plasma membrane, such as its fluidity; rather, PGA1 acts specifically to inhibit cyclic AMP extrusion. The data also imply that a transporter not relying on the Na+ gradient and distinct from transporters of cations, anions, amino acids, sugars, and nucleosides mediates cyclic AMP export.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1985

In vitro and in vivo inhibitory effects of propentofylline on cyclic AMP phosphodiesterase activity.

1-(5'-Oxohexyl)-3-methyl-7-propylxanthine (propentofylline), a vasoactive agent, was investigated for its in vitro and in vivo inhibitory effects on cyclic AMP phosphodiesterases activity. Soluble cyclic AMP phosphodiesterases from the cerebral cortex, heart muscle, descending aorta and platelet showed two Km values, high and low. The low Km values were in the range of 2.1-3.0 mumol/l and the high Km values were 111, 28.7, 30.2 and 18.7 mumol/l, respectively. Propentofylline inhibited the enzyme from the 4 tissues noncompetitively. Ki values for the low and high Km cyclic AMP phosphodiesterases were 83.4-135 and 107-188 mumol/l, respectively. In the four tissues, the enzyme inhibitory effect of propentofylline was 1/4 to 1/10 times that of 3-isobutyl-1-methylxanthine (IBMX) but 3-9 and 6-17 times as potent as those of theophylline and caffeine, respectively. The in vivo cyclic AMP phosphodiesterase inhibitory effect of propentofylline was determined in mice using an elevation of plasma cyclic AMP levels as a measure. When given both singly and in combination with isoprenaline (isoproterenol), propentofylline was a potent inhibitor of cyclic AMP phosphodiesterase in the case of intravenous administration.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1982

The role of cyclic nucleotide phosphodiesterase in the inhibition of cyclic AMP accumulation by carbachol and phosphatidate.

The possibility that activation of cyclic 3':5'-nucleotide phosphodiesterase is a component of muscarinic inhibition of cyclic AMP accumulation was investigated in WI-38 fibroblasts. At 0.2 to 20 microM, 1-isoamyl-3-isobutylxanthine, an inhibitor of fibroblast phosphodiesterase activity, attenuated the fall in WI-38 cyclic AMP content seen in response to 1 microM carbachol. The inhibitory effect of carbachol on WI-38 cyclic AMP metabolism was also suppressed by the inclusion of 0.1 to 10 microM trifluoperazine in cell incubation media. Exposure of WI-38 cultures to 1 microM carbachol was associated with elevated phosphodiesterase activity in the corresponding broken cell preparations. Both 1-isoamyl-3-isobutylxanthine and trifluoperazine interfered with the ability of 10 microM phosphatidate to mimic carbachol-inhibition of WI-38 cyclic AMP accumulation. Fibroblast calmodulin-dependent phosphodiesterase preparations were activated by micromolar dispersions of phosphatidate. This action of the phospholipid did not appear to require calcium and was blocked by trifluoperazine. These data lend support to the notion that increased cyclic nucleotide phosphodiesterase activity is at least partially responsible for the fall in WI-38 cyclic AMP levels seen in response to cholinergic stimulation. The results also suggest that the effects of cholinergic agents on WI-38 cyclic AMP hydrolysis may be related to changes in phospholipid metabolism, notably the accumulation of phosphatidate.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Expression and subcellular localization of CDK2 and cdc2 kinases and their common partner cyclin A in thyroid epithelial cells: comparison of cyclic AMP-dependent and -independent cell cycles.

Dog thyroid epithelial cells in primary culture constitute a model of positive control of DNA synthesis initiation and G0-S prereplicative phase progression by cyclic AMP as a second messenger for TSH. In tis early steps, this mitogenic control is quite distinct from cyclic AMP-independent mitogenic cascades elicited by growth factors. We demonstrate here that TSH (cyclic AMP) and EGF+serum (cyclic AMP-independent) stimulations cooperate and finally converge on proteins that control the cell cycle machinery. This convergence included a common induction of the expression of cyclin A and p34cdc2, and to a lesser extent of p33/38cdk2, which was already expressed in quiescent thyroid cells, and common changes of cdc2 and CDK2 phosphorylations as evidenced by electrophoretic mobility shifts. Kinetic differences in these processes after stimulation by TSH or EGF+serum or by these factors in combination correlated with differences in cell cycle kinetics. Moreover, an immunofluorescence analysis of these proteins using the double labeling of PCNA as a marker of each cell cycle phase shows: (1) a previously undescribed nuclear translocation of CDK2 before S phase initiation; (2) a sudden increase of cdc2 nuclear immunoreactivity at G2/mitosis transition. These data support the roles of CDK2 and cdc2 at G1/S and G2/mitosis transitions, respectively. (3) We were unable to demonstrate in individual cells a strict association between the nuclear appearance of cyclin A and G1/S transition, and an association of cyclin A and CDK2 with PCNA-stained DNA replication sites. On the other hand, the lengthening of G2 phase in the TSH/cyclic AMP-dependent thyroid cell cycle was associated with a stabilization of Tyr15 inhibitory phosphorylation of cdc2 and an especially high nuclear concentration of cyclin A and CDK2. We hypothesize that high nuclear accumulation of cyclin A and CDK2 during G2 phase could be causative in the cyclic AMP-dependent delay of mitosis onset.

Animals↗
PubMed1985

Down-regulation of gonadotropin and beta-adrenergic receptors by hormones and cyclic AMP.

Loss of gonadotropin receptors in murine Leydig tumor cells and of beta-adrenergic receptors in rat glioma C6 cells occurred following exposure of the cells to human chorionic gonadotropin and isoproterenol, respectively. Down-regulation of receptors was mimicked in part by other agents that elevated cyclic AMP levels in the cells such as cholera toxin and dibutyryl cyclic AMP. Whereas agonist-mediated receptor loss was rapid and almost total, down-regulation by cyclic AMP was slower and less extensive. Down-regulation of receptors did not appear to be accompanied by loss of the regulatory and catalytic components of adenylate cyclase. Hormone-mediated down-regulation was preceded by desensitization of hormone-stimulated adenylate cyclase. In contrast, there was no evidence that cyclic AMP caused desensitization. Finally, loss of receptors induced either by agonists or cyclic AMP required protein synthesis as cycloheximide inhibited down-regulation. We conclude that down-regulation of receptors in these cells is a complex process involving both cyclic AMP-independent and -dependent events.

Animals↗
PubMed1979

Gonadotropin stimulation of cyclic AMP levels in Chinese hamster ovary cells in culture.

When Chinese Hamster Ovary (CHO) cells, incubated in serum-free medium, are exposed to gonadotropins a transient increase in the intracellular concentration of cyclic AMP is observed. Maximum accumulation of cyclic AMP is noted 30 minutes after addition of either human chorionic gonadotropin (hCG) or follicle stimulating hormone (FSH). Within one to two hours after hormone addition, the intracellular concentrations of cyclic AMP have returned to basal levels. The enhancement of intracellular cyclic AMP levels by hCG is hormone concentration dependent, with maximal stimulation observed at 10 micrograms/ml hCG. The exogenous addition of gonadotropins also slows the growth rate of CHO cells. This effect on growth seems to be mediated through cyclic AMP since the growth rate of a mutant of CHO cells defective in the catalytic subunit of cyclic AMP dependent protein kinase is only slightly decreased.

Animals↗
PubMed1979

Hemicyst formation stimulated by cyclic AMP in dog kidney cell line MDCK.

Certain epithelial cell lines have morphologic, physiologic, biochemical and pharmacologic characteristics of transporting epithelia from intact organs. In this paper we show that dibutyryl cyclic AMP, 5' AMP, adenosine and cyclic AMP phosphodiesterase inhibitors stimulate hemicyst formation by the dog kidney cell line MDCK. It is suggested that this effect is explained by elevation of intracellular cyclic AMP levels by means of an exogenous non-metabolizable source of cyclic AMP, phosphodiesterase inhibition or adenyl cyclase stimulation. Since hemicyst formation is in part due to transepithelial fluid transport, these findings raise the possibility that this fraction might be modulated by cAMP in an established cell line. We believe that cultured epithelial cells may provide an exploitable model system to investigate at the cellular and subcellular levels, the mechanism by which cyclic AMP modifies water and solute movements across epithelia.

Adenine Nucleotides↗
PubMed1981

Multiple mechanisms of growth inhibition by cyclic AMP derivatives in rat GH1 pituitary cells: isolation of an adenylate cyclase-deficient variant.

GH pituitary cells have been widely utilized for studies of hormone response mechanisms. Studies reported here were motivated by the desirability of isolating characterized GH clones defective in cyclic AMP synthesis or action. Spontaneously occurring GH1 cell variants resistant to the growth-inhibitory effects of cyclic AMP analogs were isolated. Characterization of four variants showed that these were deficient in adenosine kinase and had acquired resistance to the cytotoxic effects of purine nucleoside derivatives formed in the culture medium. A second-stage selection was undertaken with mutagenized adenosine kinase-deficient cells. One 8 Br cAMP-resistant variant was found to have normal cyclic AMP-dependent protein kinase activity but exhibited altered adenylate cyclase activity. Activation of cyclase activity by fluoride, guanyl nucleotides, cholera toxin, and hormone (VIP) was subnormal in the variant. Mn-dependent cyclase activity was also subnormal, suggesting that the 8 Br cAMP-resistant variant may have a deficiency in the catalytic moiety of adenylate cyclase. Surprisingly, adenosine 3':5'-monophosphate and 5'-monophosphate derivatives were found to be equally potent in growth-inhibiting adenosine kinase-deficient cells. Cross-resistance to 8 Br AMP was observed in the 8 Br cAMP-resistant variant. We conclude that cyclic AMP derivatives inhibit growth of GH cells by an unanticipated mechanism that is, nonetheless, related to endogenous cyclic AMP synthesis.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1982

Genetic evidence that a phorbol ester tumor promoter stimulates ornithine decarboxylase activity by a pathway that is independent of cyclic AMP-dependent protein kinases in CHO cells.

Ornithine decarboxylase (ODC) inductions by cholera toxin and by the phorbol ester tumor promoter, TPA, were compared in wild-type Chinese hamster ovary (CHO) cells and in mutant cells having altered cyclic AMP-dependent protein kinase activity. The aim of these studies was to determine whether cyclic AMP-dependent protein kinase is involved in these inductions. The time course and the magnitude of ODC inductions by either 100 ng/ml cholera toxin or 100 ng/ml TPA were similar in wild-type cells with a maximum at 3-4 hours after treatment and a return to unstimulated levels by 8 hours. Induction of ODC by cholera toxin was suppressed more than 80% in the four protein kinase mutants studied (10215, 10248, 10260, and 10265), strongly implicating a cyclic AMP-dependent kinase step in the mechanism of induction. Similar results were found with the cyclic AMP analog 8-Br-cyclic AMP and the phosphodiesterase inhibitor, methyl-isobutylxanthine. The induction of ODC by TPA, on the other hand, was only partially inhibited (approximately 50%) in three of four mutants. Lower ODC activity in two mutants stimulated by cholera toxin or TPA whose kinetics were studied in more detail could not be ascribed to a reduced affinity (Km) of ornithine for the enzyme, but appeared to be due to reduced catalytic activity (Vmax) in the extracts. These results suggest that the induction of ODC by TPA proceeds by a mechanism which is only partially dependent on an intact cyclic AMP-dependent protein kinase activity.

Animals↗
PubMed1984

Differential sensitivity of fibroblasts to epidermal growth factor is related to cyclic AMP concentration.

The differential sensitivity of various cell lines to the mitogenic effects of epidermal growth factor (EGF) was investigated. Two lines of evidence suggest that cellular capacity to respond proliferatively to EGF is related to intracellular cyclic AMP concentration. First, the ability of three density-arrested cell lines to synthesize DNA in response to EGF was directly proportional to the basal cyclic AMP level of the cells at quiescence. Second, treatment of cultures with various agents known to promote intracellular cyclic AMP accumulation increased the sensitivity of all three cell lines to EGF. The mechanism whereby cyclic AMP modulates EGF responsiveness is not known; cholera toxin did not affect the cellular capacity to bind or internalize and process EGF. Although platelet-derived growth factor (PDGF) had no effect on cyclic AMP levels, transient treatment of quiescent cultures with this polypeptide also enhanced EGF sensitivity. In agreement with previous data and in contrast to cholera toxin, PDGF induced the down-regulation of EGF receptors in the three cell lines. These data suggest that the capacity of various cell types to respond to EGF is subject to both intracellular regulation by cyclic AMP and extracellular modulation by factors such as PDGF which can affect EGF receptor activity.

Animals↗
PubMed1994

Extracellular calcium modulates prereplicative cyclic AMP surges in EGF-stimulated primary neonatal rat hepatocytes.

The cells in nearly pure (96-98%) primary cultures of hepatocytes from neonatal rat liver in high (1.0 mM)-Ca2+, serum-free, synthetic HiWo5Ba2000 medium initiated DNA synthesis and entered mitosis between 11 and 30 h after the addition of 10 ng/ml EGF. During the 10-h prereplicative period, the cultured hepatocytes, like regenerating rat liver cells, generated two large cyclic AMP transients, one peaking between 30 min and 2 h and the other around 6 h. Hepatocytes stimulated by the same concentration of EGF in low (0.02 mM)-Ca2+ medium increased cyclic AMP synthesis as much as the EGF-treated hepatocytes in high-Ca2+ medium, but they released the additional cyclic AMP into the medium and could not generate prereplicative internal cyclic AMP surges, initiate DNA replication, or enter mitosis. These results suggest that one of the ways external Ca2+ controls prereplicative development of hepatocytes is to restrain the release of cyclic AMP and thus enable the cell to accumulate enough internal cyclic AMP to stimulate events required to initiate DNA replication.

Animals↗