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PubMed1988

The mechanism of action of AMP-induced inhibition of sympathetic neurotransmission in the isolated vas deferens of the rat and guinea-pig.

1. The proposal that adenosine 5'-monophosphate (AMP) can be used as a selective antagonist of ATP at P2-purinoceptors on smooth muscle was investigated by examining the electrical and mechanical responses of guinea-pig and rat vasa deferentia to stimulation of sympathetic nerves and to exposure to exogenous agonists. 2. The magnitude of the contractile response of the rat vas deferens to field stimulation of the sympathetic nerves was reduced by addition of AMP. This effect was rapid in onset and readily reversed by washout. 3. The action of AMP on these contractile responses was reversed by the subsequent addition of the specific P1-purinoceptor antagonist 8-phenyltheophylline (8-PT). 8-PT on its own had no significant effect on contractile responses to nerve stimulation. 4. The magnitude of excitatory junction potentials (e.j.ps) in the guinea-pig vas deferens evoked by a train of stimuli at 0.5 Hz was reduced in a dose-dependent manner by introduction of AMP (10(-6)-10(-3)M). The inhibitory effect of 10(-5) M AMP on e.j.p. magnitude was completely and rapidly reversed by introduction of 10(-5)M 8-PT. The effect of 10(-4)M AMP was partially reversed by 10(-5) 8-PT. 5. The contractile responses of the guinea-pig vas deferens to exogenously applied adenosine 5'-triphosphate (ATP) were not reduced by AMP, even at a concentration of 2.5 X 10(-4)M. Similarly in the rat vas deferens, contractile responses to exogenously applied alpha, beta-methylene ATP (a more potent P2-purinoceptor agonist) were reduced by only 27.2%. The same concentration of AMP did not affect the contractile responses of the rat vas deferens to noradrenaline. 6. We conclude that the primary mechanism of action of AMP is to inhibit sympathetic neurotransmission by an agonist action at P1-purinoceptors on the sympathetic nerve terminal reducing the release of neurotransmitter, and therefore AMP cannot be used as a selective P2-purinoceptor antagonist.

Action Potentials↗
PubMed1993

Effects of a water-soluble forskolin derivative (NKH477) and a membrane-permeable cyclic AMP analogue on noradrenaline-induced Ca2+ mobilization in smooth muscle of rabbit mesenteric artery.

1. Effects were studied of 6-(3-dimethylaminopropionyl) forskolin (NKH477), a water-soluble forskolin derivative and of dibutyryl-cyclic AMP, a membrane-permeable cyclic AMP analogue on noradrenaline (NA)-induced Ca2+ mobilization in smooth muscle strips of the rabbit mesenteric artery. The intracellular concentration of Ca2+ ([Ca2+]i), isometric force and cellular concentration of inositol 1,4,5-trisphosphate (InsP3) were measured. 2. NA (10 microM) produced a phasic, followed by a tonic increase in both [Ca2+]i and force in a solution containing 2.6 mM Ca2+. NKH477 (0.01-0.3 microM) attenuated the phasic and the tonic increases in both [Ca2+]i and force induced by 10 microM NA, in a concentration-dependent manner. 3. In Ca(2+)-free solution containing 2 mM EGTA with 5.9 mM K+, NA (10 microM) produced only phasic increases in [Ca2+]i and force. NKH477 (0.01 microM) and dibutyryl-cyclic AMP (0.1 mM) each greatly inhibited these increases. 4. NA (10 microM) led to the production of InsP3 in intact smooth muscle strips and InsP3 (10 microM) increased Ca2+ in Ca(2+)-free solution after a brief application of Ca2+ in beta-escin-skinned smooth muscle strips. NKH477 (0.01 microM) or dibutyryl-cyclic AMP (0.1 mM) modified neither the NA-induced synthesis of InsP3 in intact muscle strips nor the InsP3-induced Ca2+ release in skinned strips. 5. In Ca(2+)-free solution, high K+ (40 and 128 mM) itself failed to increase [Ca2+]i but concentration-dependently enhanced the amplitude of the increase in [Ca2+]i induced by 10 microM NA with a parallel enhancement of the maximum rate of rise. The extent of the inhibition induced by NKH477 (0.01 microM)or dibutyryl-cyclic AMP (0.1 mM) on the NA-induced [Ca2+] increase was inversely related to the maximum rate of rise of [Ca2+], induced by NA in Ca2+-free solution containing various concentrations of K+. These results suggest that the increase in the rate of Ca2+ release induced by NA can conceal the inhibitory action on NA-induced Ca2+ mobilization of agents that increase cyclic AMP.6. Repetitive application of 10 JAM NA in Ca2+-free solution led to a disappearance of the NA-induced increase in [Ca2+]j, but NA could again increase [Ca2+], in Ca2+-free solution after a brief application of Ca2+ with 40 mM K+ ('Ca2+-loading'). The magnitude of this NA-induced increase in [Ca2+]i depended on the duration of the Ca2+-loading. With application of dibutyryl-cyclic AMP (0.1 mM) during the Ca2+-loading period, the loading duration required for the restoration of the maximum NA-response was shortened.7. Cyclopiazonic acid (10 microM, an inhibitor of Ca2+-ATPase at intracellular storage sites) attenuated the inhibitory action of dibutyryl-cyclic AMP on the NA-induced increase in [Ca2+], in Ca2+-free solution.When NA (10 microM) was applied twice for 30 s with a 10 min interval in Ca2+-free solution, the amplitude of response to the second application was about one third of the first response. With application of 0.1 mM dibutyryl-cyclic AMP during the first application of NA, the increase in [Ca2+], induced by the first application of NA was inhibited, but the response induced by the second was enhanced. These results suggest that dibutyryl-cyclic AMP enhances Ca2+ uptake into the NA-sensitive storage sites.8. We conclude that, in smooth muscle of the rabbit mesenteric artery, agents that increase cyclic AMP inhibit the NA-induced increase in [Ca2+] through an activation of Ca2+ uptake into the cellular storage sites.

Animals↗
PubMed1985

Transport of AMP by Rickettsia prowazekii.

Rickettsia prowazekii possesses an exchange transport system for AMP. Chromatographic analysis of the rickettsiae demonstrated that transported AMP appeared intracellularly as AMP, ADP, and ATP, and no hydrolytic products appeared in either the intracellular or extracellular compartments. The phosphorylation of AMP to ADP and ATP was prevented by pretreatment of the cells with 1 mM N-ethylmaleimide without inhibiting the transport of AMP. Although no efflux was demonstrable in the absence of nucleotide in the medium, the intracellular adenine nucleotide pool could be exchanged with external unlabeled adenine nucleotides. Both ADP and ATP were as effective as AMP at inhibiting the uptake of [3H]AMP. Although this transport system was inhibited by low temperature (0 degrees C) and partially inhibited by the protonophore carbonyl cyanide-m-chlorophenyl hydrazone (1 mM), it was relatively insensitive to KCN (1 mM). The uptake of AMP at 34 degrees C had an apparent Kt for influx of 0.4 mM and a Vmax of 354 pmol min-1 per mg. At 0 degrees C there was a very rapid and unsaturable association of AMP with these organisms. Correction of the uptake data at 34 degrees C for the 0 degrees C component lowered the apparent Kt to 0.15 mM. Both magnesium and phosphate ions are required for optimal transport activity. Chemical measurements of the total intracellular nucleotide pools demonstrated that this system was not a net adenine nucleotide transport system, but that uptake of AMP was the result of an exchange with internal adenine nucleotides.

Adenosine Diphosphate↗
PubMed2005

AMP-18 protects barrier function of colonic epithelial cells: role of tight junction proteins.

Antrum mucosal protein (AMP)-18 and a synthetic peptide of amino acids 77-97 have mitogenic and motogenic properties for epithelial cells. The possibility that AMP-18 is also protective was evaluated in the colonic mucosa of mice and monolayer cultures of human colonic epithelial Caco-2/bbe (C2) cells. Administration of AMP peptide to mice with dextran sulfate sodium (DSS)-induced colonic injury delayed the onset of bloody diarrhea and reduced weight loss. Treatment of C2 cells with AMP peptide protected monolayers against decreases in transepithelial electrical resistance induced by the oxidant monochloramine, indomethacin, or DSS. A molecular mechanism for these barrier-protective effects was sought by asking whether AMP peptide acted on specific tight junction (TJ) proteins. Immunoblots of detergent-insoluble fractions of C2 cells treated with AMP peptide exhibited increased accumulation of specific TJ proteins. Occludin immunoreactivity was also increased in detergent-insoluble fractions obtained from colonic mucosal cells of mice injected with AMP peptide. Observations using laser scanning confocal (CF) microscopy supported the capacity of AMP peptide to enhance accumulation of occludin and zonula occludens-1 in TJ domains of C2 cell monolayers and together with immunoblot analysis showed that the peptide protected against loss of these TJ proteins following oxidant injury. AMP peptide also protected against a fall in TER during disruption of actin filaments by cytochalasin D and stabilized perijunctional actin during oxidant injury when assessed by CF. These findings suggest that AMP-18 could protect the intestinal mucosal barrier by acting on specific TJ proteins and stabilizing perijunctional actin.

Actins↗
PubMed1976

Cyclic AMP in secretin choleresis. Evidence for a regulatory role in man and baboons but not in dogs.

Cyclic AMP output in the bile in response to intravenous secretin was measured in 11 patients, 12 baboons, and 15 dogs. Secretin was given to patients with bile drainage tubes as an intravenous bolus (1 U per kg). In baboons and dogs both secretin infusion (4 U per kg per hr) and bolus injection (1 U per kg) were used. In baboons cyclic AMP was also determined in liver, extrahepatic duct tissue, and in perfusate from isolated segments of extrahepatic bile ducts. Secretin induced a marked choleresis in all three species. In humans, biliary cyclic AMP concentration increased an average (+/- 1 SE) of 68% +/- 12% and in baboons 4-fold, but no increase occurred in dogs. In baboons, cyclic AMP concentration increased in both bile duct tissue and perfusate from isolated bile ducts concomitant with secretin choleresis, but not in liver. In humans the choleretic effects of sodium dehydrocholate, aminophylline, and glucagon were compared to dibutyryl cyclic AMP (DBcyclic AMP). All agents increased bile flow 2- to 3-fold. Cyclic AMP concentration in bile markedly increased after glucagon and DBcyclic AMP but not after sodium dehydrocholate and aminophylline. We conclude that cyclic AMP is implicated in secretin choleresis in both humans and baboons, but not in dogs. The bile duct appears to be the site of cyclic AMP elaboration induced by secretin in baboons and probably is also in man.

Aminophylline↗
PubMed1990

Role of AMP on the activation of glycogen synthase and phosphorylase by adenosine, fructose, and glutamine in rat hepatocytes.

The mechanism for glycogen synthesis stimulation produced by adenosine, fructose, and glutamine has been investigated. We have analyzed the relationship between adenine nucleotides and glycogen metabolism rate-limiting enzymes upon hepatocyte incubation with these three compounds. In isolated hepatocytes, inhibition of AMP deaminase with erythro-9-(2-hydroxyl-3nonyl)adenine further increases the accumulation of AMP and the activation of glycogen synthase and phosphorylase by fructose. This ketose does not increase cyclic AMP or the activity of cyclic AMP-dependent protein kinase. Adenosine raises AMP and ATP concentration. This nucleotide also activates glycogen synthase and phosphorylase by covalent modification. The correlation coefficient between AMP and glycogen synthase activity is 0.974. Nitrobenzylthioinosine, a transport inhibitor of adenosine, blocks (by 50%) the effect of the nucleoside on AMP formation and glycogen synthase but not on phosphorylase. 2-Chloroadenosine and N6-phenylisopropyladenosine, nonmetabolizable analogues of adenosine, activate phosphorylase (6-fold) without increasing the concentration of adenine nucleotides or the activity of glycogen synthase. Cyclic AMP is not increased by adenosine in hepatocytes from starved rats but is in cells from fed animals. [Ethylenebis (oxyethylenenitrilo)]tetraacetic acid (EGTA) blocks by 60% the activation of phosphorylase by adenosine but not that of glycogen synthase. Glutamine also increases AMP concentration and glycogen synthase and phosphorylase activities, and these effects are blocked by 6-mercaptopurine, a purine synthesis inhibitor. Neither adenosine nor glutamine increases glucose 6-phosphate. It is proposed that the observed efficient glycogen synthesis from fructose, adenosine, and glutamine is due to the generation of AMP that activates glycogen synthase probably through increases in synthase phosphatase activity. It is also concluded that the activation of phosphorylase by the above-mentioned compounds can be triggered by metabolic changes.

Adenine↗
PubMed1987

Recovery of myocardial function after ischaemia: the effects of AMP and inhibition of endocytosis.

Recovery from ischaemia in heart tissue can be accelerated by addition of precursors of ATP such as AMP to the coronary circulation. Endocytosis in capillary endothelia is also stimulated by AMP; therefore endocytosis may be important in the transport of AMP from the circulation into myocytes. Alternatively, the increase in endocytotic transport itself could be responsible for accelerated recovery, irrespective of the stimulating agent. The effects of sham, AMP, cytochalasin-D (an inhibitor of endocytosis), and cytochalasin-D + AMP infusates given prior to, during, and following a 15 min ischaemic episode, were examined. AMP accelerated biochemical and functional recovery after episodes of ischaemia and stimulated endocytosis in coronary capillaries. Cytochalasin-D strongly inhibited contractility before, during, and after ischaemia, and similarly depressed ATP and creatine phosphate levels. Cytochalasin-D also strongly inhibited endocytosis and caused swelling of the capillary endothelium. When cytochalasin-D and AMP were provided together, the beneficial effects of AMP were only partially inhibited by cytochalasin-D. In fact, AMP was able to reverse most of the effects of cytochalasin-D including the inhibition of endocytosis. This suggests accelerated recovery of ischaemic myocytes requires precursors of ATP such as AMP, and the stimulation of endocytosis may abet transport of these precursors, or may be a spurious phenomenon.

Adenosine Monophosphate↗
PubMed1993

Ultrastructural localization of 5'AMP odorant receptor sites on the dendrites of olfactory receptor neurons of the spiny lobster.

A unique probe--biotinylated adenosine-5'-monophosphate (5'AMP-biotin)--was used in transmission electron microscopic (TEM) studies to localize 5'AMP odorant binding sites on the dendrites of olfactory receptor neurons in the aesthetasc sensilla of the spiny lobster, Panulirus argus. This probe is capable of both binding to and exciting 5'AMP-sensitive olfactory receptor neurons, as revealed through biochemical and electrophysiological assays. TEM studies showed that 5'AMP-biotin binding sites are distributed along the entire dendritic region that is exposed to odorants, including the transitional zone (between the inner and outer dendritic segments, including the ciliary segment) and all of the outer dendritic segment. The density of 5'AMP binding sites per micron2 of membrane is similar along the length of the olfactory dendrite. However, the relative number of 5'AMP-biotin binding sites per micron2 of sensillar area diminishes in the distal 30% of the aesthetasc due to a decrease in the amount of dendritic membrane in that region. The distribution of these 5'AMP binding sites is therefore much more extensive than that of enzymes that inactivate 5'AMP--5'ectonucleotidase/phosphatase--which are restricted to the transitional zone (Gleeson et al., 1991). Taken together, these results suggest that 5'AMP-biotin is labeling 5'AMP-specific olfactory receptor sites that are located along the entire outer dendritic segment and that can be coupled to olfactory transduction. This study represents the first in situ localization of specific olfactory receptor sites using a specific, functionally defined ligand.

Adenosine Monophosphate↗
PubMed1983

Cyclic AMP levels in relation to membrane phospholipid variations in Neurospora crassa.

The correlation between membrane phospholipid composition and total cyclic AMP levels was investigated by using Neurospora lipid auxotrophs under various supplementation conditions. The lipid composition of the supplemented cultures was determined, and the intracellular and extracellular cyclic AMP levels were measured at various stages of the culture growth. Kinetic parameters and the thermostability of adenylate cyclase and of cyclic AMP-dependent phosphodiesterase were measured under all supplementation conditions. In inositol deficient inl cultures the levels of intracellular cyclic AMP decreased exponentially towards the end of the log phase and thereafter. In chol-l; chol-2 cultures, grown in N-monomethylethanolamine and low choline supplementation, the level of intracellular cyclic AMP decreased as function of decreasing exogenous choline supplement. Rates of cyclic AMP extrusion in all cultures were comparable on dry weight basis, and thus not affected by the mycelial lipid composition. Adenylate cyclase activity and thermostability decreased under those supplementation conditions resulting in reduction of cyclic AMP. Cyclic AMP-dependent phosphodiesterase was insensitive to phospholipid changes. Accordingly, it is suggested that specific perturbations in cellular phospholipid composition affect the membrane-bound adenylate cyclase and hence the cyclic AMP synthesis in vivo.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1977

Solubilization and photoaffinity labeling of renal membrane cyclic AMP receptors.

Renal cortical plasma membranes were solubilized with sodium deoxycholate. The membrane-bound cyclic AMP receptors retained biologic activity in the detergent-dispersed state exhibiting the properties of high affinity for cyclic AMP, saturability and specificity. Half-maximal binding of cycle [3H]-AMP to these receptors was found to occur at 0.06 muM and 1.5 pmol of cyclic [3H]AMP was bound per mg membrane protein at saturation (0.5 muM cyclic [3H]AMP). Sodium deoxycholate-solubilized membrane proteins were chromatographed on Biogel A-5m. Cyclic [3H]AMP receptors eluted in the internal volume at positions equivalent to molecular sizes of 50 000 and 20 000 daltons and in the void volume at molecular size greater than 450 000. After photoaffinity labeling the renal membrane receptors with cyclic [3H]AMP, we found peaks of tritium radioactivity which eluted at similar molecular size positions on this Bogel A-5m column. Further treatment of photoaffinity labeled membranes with sodium dodecyl sulfate, mercaptoethanol and urea, followed by polyacrylamide gel electrophoresis, showed bands of tritium-labeled receptor protein with relative mobilities corresponding to molecular sizes of 26 000 and 21 000 daltons. This study shows that porcine renal cortical membranes contain at least two molecular species of cyclic AMP receptors which may be associated with regulation of the membrane-bound cyclic AMP-dependent protein kinase.

Affinity Labels↗
PubMed1982

Relationship between stimulated prolactin release from GH cells and cyclic AMP degradation and formation.

We have studied the relationship between the prolaction (PRL) release induced by thyroliberin (TRH) and theophylline and the formation and inactivation of adenosine 3', 5'-cyclic monophosphate (cyclic AMP) in cultured rat-pituitary cells (GH3 cells). TRH, which stimulated prolactin release, increased cyclic AMP formation and stimulated transiently both the low- and high-Km cyclic phosphodiesterases. The maximal effect on the phosphodiesterase was observed at 30 mM TRH. The stimulatory effect of TRH on the activity of the cyclic AMP phosphodiesterases was duplicated by incubation of the cells with cyclic AMP (2-10 mM). In washed particulate GH3 cell fractions, TRH increased the adenylyl cyclase activity up to 180%. Treatment of GH3 cells with theophylline stimulated the release of PRL and inhibited cyclic AMP degradation probably leading to the measured increase in cellular concentrations of the nucleotide. The effects of TRH and theophylline on cellular cyclic AMP concentrations and on PRL release were additive. There was a positive correlation between PRL release and cellular cyclic AMP concentration (r = 0.97). The elevations observed in cellular cyclic AMP concentration after TRH treatment are due to increased formation which in turn leads to phosphodiesterase activation. Therefore, cyclic AMP formation appears to be an intermediary step in the stimulus-secretion coupling caused by the tripeptide.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1980

The effect of diamide on cyclic AMP levels and cyclic nucleotide phosphodiesterase in human peripheral blood lymphocytes.

The effect of diamide (diazene dicarboxylic acid bis[N,N'-dimethylamide) on cyclic AMP levels and cyclic nucleotide phosphodiesterase in human peripheral blood lymphocytes was examined. In the absence of mitogenic lectins, 5 . 10(-3)-1 . 10(-4) M diamide markedly increased intracellular cyclic AMP with variable effects at higher levels. In the presence of phytohemagglutinin or concanavalin A, 5 . 10(-4) M or higher diamide concentrations consistently decreased cyclic AMP levels, usually to control levels or below, while 1 . 10(-4)-1 . 10(-5) M diamide augmented the lectin-induced rise in cyclic AMP. When intact lymphocytes were incubated with diamide, phosphodiesterase activity against both cyclic AMP and cyclic GMP, assayed in homogenates of these cells, was inhibited at concentrations as low as 1 . 10(-6) M. In contrast, when diamide was incubated with phosphodiesterase extracted from lymphocytes there was a dual effect. At low substrate concentrations and high diamide concentrations diamide was a non-competitive inhibitor of phosphodiesterase with a Ki of 1.3--2.5 mM for cyclic AMP and 3.3--10 mM for cyclic GMP. In contrast, at high substrate concentrations diamide was an 'uncompetitive' activator of phosphodiesterase activity for both cyclic AMP and cyclic GMP. The effects of diamide could be largely or completely blocked by glutathione or dithiothreitol, indicating that sulfhydryl reactivity was involved in diamide's action on lymphocyte phosphodiesterase activity and intracellular cyclic AMP levels. These data demonstrate that diamide is a phosphodiesterase inhibitor both on phosphodiesterase extracted from lymphocytes and when incubated with intact lymphocytes and that diamide may increase or decrease intracellular cyclic AMP levels depending on the concentration of diamide used.

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

Binding of cyclic AMP and cyclic GMP to renal cortical homogenates. Relationship with phosphorylation.

This study examined the binding of both cyclic AMP and cyclic GMP to receptor proteins in particulate and soluble subfractions of renal cortical homogenates from the golden hamster. The binding of both nucleotides was compared to subsequent effects of both nucleotides on the phosphorylation of histone from identical fractions. Cyclic AMP binding and cyclic AMP-dependent protein kinase activity predominated in the cytosol, with some binding and enzyme activity also detected in particulate fractions. Cyclic GMP and cyclic GMP-dependent protein kinase activity could only be demonstrated in cytosolic fractions and represented only 20-30% of cyclic AMP-dependent activity in this fraction. Binding of both nucleotides was highly specific, however, cyclic AMP showed some interaction with cyclic GMP binding. Evidence suggesting that each nucleotide interacts with a specific protein kinase was as follows: both the binding activity of the cyclic nucleotides and their combined protein kinase activity show additivity; cyclic AMP and cyclic GMP binding activity could be separated on sucrose gradients; cyclic AMP and cyclic GMP protein kinase activity could be separated with Sephadex G-100 chromatography, after preincubation of homogenate supernatants with either cyclic AMP or cyclic GMP. The results demonstrate the presence of both cyclic AMP- and cyclic GMP-dependent protein kinase in renal cortex.

Animals↗
PubMed1998

Cyclic AMP-elevating agents prevent oligodendroglial excitotoxicity.

Previously, we have demonstrated that cells of the oligodendroglial lineage express non-NMDA glutamate receptor genes and are damaged by kainate-induced Ca2+ influx via non-NMDA glutamate receptor channels, representing oligodendroglial excitotoxicity. We find in the present study that agents that elevate intracellular cyclic AMP prevent oligodendroglial excitotoxicity. After oligodendrocyte-like cells, differentiated from the CG-4 cell line established from rat oligodendrocyte type-2 astrocyte progenitor cells, were exposed to 2 mM kainate for 24 h, cell death was evaluated by measuring activity of lactate dehydrogenase released into the culture medium. Released lactate dehydrogenase increased about threefold when exposed to 2 mM kainate. Kainate-induced cell death was prevented by one of the following agents: adenylate cyclase activator (forskolin), cyclic AMP analogues (dibutyryl cyclic AMP and 8-bromo-cyclic AMP), and cyclic AMP phosphodiesterase inhibitors (3-isobutyl-1-methylxanthine, pentoxifylline, propentofylline, and ibudilast). Simultaneous addition of both forskolin and phosphodiesterase inhibitors prevented the kainate-induced cell death in an additive manner. A remarkable increase in Ca2+ influx (approximately 5.5-fold) also was induced by kainate. The cyclic AMP-elevating agents caused a partial suppression of the kainate-induced increase in Ca2+ influx, leading to a less prominent response of intracellular Ca2+ concentration to kainate. The suppressing effect of forskolin on the kainate-induced Ca2+ influx was partially reversed by H-89, an inhibitor of cyclic AMP-dependent protein kinase. In contrast to this, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, brought about a decrease in the kainate-induced Ca2+ influx. We therefore concluded that cyclic AMP-elevating agents prevented oligodendroglial excitotoxicity by cyclic AMP-dependent protein kinase-dependent protein phosphorylation, resulting in decreased kainate-induced Ca2+ influx.

Animals↗
PubMed2001

Cyclic AMP regulation of neutrophil apoptosis occurs via a novel protein kinase A-independent signaling pathway.

The second messenger molecule cyclic AMP dramatically modulates the apoptotic program in a wide variety of cells, accelerating apoptosis in some and delaying the rate of apoptosis in others. Human neutrophil apoptosis, a process that regulates the fate and numbers of these potentially histotoxic cells in inflammatory sites, is profoundly delayed by the cell-permeable analog of cyclic AMP, dibutyryl-cAMP. We have investigated the mechanisms underlying cyclic AMP-mediated delay of neutrophil apoptosis, and we show that cyclic AMP inhibits loss of mitochondrial potential occurring during constitutive neutrophil apoptosis. Furthermore, we demonstrate that cyclic AMP also suppresses caspase activation in these inflammatory cells. Despite increasing protein kinase A activity, this kinase is unlikely to mediate the effect of cyclic AMP on apoptosis because blockade of protein kinase A activation did not influence the survival effects of cyclic AMP. Further investigation of the signaling mechanism demonstrated that the delay of apoptosis is independent of phosphoinositide 3-kinase and MAPK activation. Our results suggest cyclic AMP delays neutrophil apoptosis via a novel, reversible, and transcriptionally independent mechanism. We show that proteasome activity in the neutrophil is vitally involved in this process, and we suggest that a balance of pro-apoptotic and anti-apoptotic proteins plays a key role in the powerful ability of cyclic AMP to delay neutrophil death.

Adenosine Monophosphate↗
PubMed1998

The inhibition of DNA synthesis by prostaglandin E2 in human gingival fibroblasts is independent of the cyclic AMP-protein kinase A signal transduction pathway.

In this study we attempted to clarify the mechanism of the inhibitory effects of PGE2 on DNA synthesis in Gin-1 (fibroblasts derived from healthy human gingiva) from the aspect of the cyclic AMP-dependent protein kinase signal transduction pathway. PGE2 upregulated intracellular cyclic AMP accumulation and inhibited DNA synthesis in Gin-1 in a dose-dependent manner. When the PGE2-induced intracellular cyclic AMP accumulation was further enhanced by treatment with the cyclic AMP-phosphodiesterase inhibitor, IBMX, the inhibitory effect of PGE2 on DNA synthesis was also enhanced. Furthermore, when we examined the effects of forskolin, an activator of cyclic AMP production, on intracellular cyclic AMP accumulation and DNA synthesis, similar results were obtained. However, inhibitors of cyclic AMP-dependent protein kinase (protein kinase A) such as HA1004 did not diminish the inhibitory effect of PGE2 on DNA synthesis in Gin-1. These results suggest that in Gin-1, PGE2-induced cyclic AMP accumulation may not lead to the activation of protein kinase A or protein kinase A activity may not relate directly to the growth inhibitory effect of PGE2, and that PGE2 does not inhibit DNA synthesis through the cyclic AMP-protein kinase A signal transduction pathway in Gin-1.

1-Methyl-3-isobutylxanthine↗
PubMed1975

The binding of cyclic AMP to renal brush border membranes.

The binding of cyclic AMP to the proximal tubule luminal (brush border) membrane isolated from the rabbit renal cortex was studied. The rate of binding was dependent on temperature; at 37 degrees equilibrium was attained in 45 min, whereas at 0 degrees 120 min was required. The final levels of binding were identical. The binding of 3H-cyclic AMP was reversed by dilution or addition of unlabeled cyclic nucleotide. Debinding was markedly temperature sensitive. Binding was only partially saturable with respect to cyclic AMP concentration, apparently with more than one binding site. The cyclic AMP bound to the membrane was recovered unchanged. When bound to the membrane cyclic AMP was resistant to hydrolysis by endogenous membrane or exogenously added phosphodiesterase. The binding to the membranes was relatively specific for cyclic AMP, although other cyclic purine nucleotides inhibited, cyclic IMP greater than dibutyryl cyclic AMP greater than cyclic GMP. The renal membranes did bind cyclic GMP, but this binding was relatively non-specific. Hormones and drugs, that mediate cyclic AMP generation or renal function, as well as other compounds common to the proximal tubule were without significant effect on cyclic AMP binding. Binding was inhibited by sulfhydryl reacting agents and this inhibition could be blocked and partially reversed by mercaptoethanol.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Gene expression in Dictyostelium discoidium: mutually antagonistic roles of cyclic-AMP and ammonia.

Cyclic-AMP and ammonia have been previously identified as extracellular signals during Dictyostelium development. Both are important in controlling morphological movements and cyclic-AMP also in inducing gene expression. The work in tis paper is concerned with their effects on developmental gene expression. Cyclic-AMP was found to act as an inducer during the aggregative (as exemplified by phosphodiesterase) and the post-aggregative (glycogen phosphorylase, UDP-galactose polysaccharide transferase, prespore vacuoles and stalk cells) phases of gene expression. Ammonia inhibited the appearance of each of the above markers and antagonized the inductive effects of cyclic-AMP on them. This inhibition by ammonia of cyclic-AMP inducible gene expression may involve a step linking elevated intracellular cyclic-AMP levels to gene activation. It has been suggested that the specification of cells within the aggregate into the stalk and spore pathways of differentiation might be controlled by cyclic-AMP and ammonia. In this model for pattern formation cyclic-AMP would induce stalk cell differentiation and ammonia spore formation. The present results argue against this idea since cyclic-AMP induces and ammonia inhibits differentiation along both pathways. The function of these agents may rather be to coordinate the rates of biochemical differentiation of individual cells and link them to the overall morphological changes occurring during development.

3',5'-Cyclic-AMP Phosphodiesterases↗