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PubMed2006

Stimulation of adenosine A1 and A2A receptors by AMP in the submucosal plexus of guinea pig small intestine.

Actions of adenosine 5'-monophosphate (AMP) on electrical and synaptic behavior of submucosal neurons in guinea pig small intestine were studied with "sharp" intracellular microelectrodes. Application of AMP (0.3-100 microM) evoked slowly activating depolarizing responses associated with increased excitability in 80.5% of the neurons. The responses were concentration dependent with an EC(50) of 3.5 +/- 0.5 microM. They were abolished by the adenosine A(2A) receptor antagonist ZM-241385 but not by pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid, trinitrophenyl-ATP, 8-cyclopentyl-1,3-dimethylxanthine, suramin, or MRS-12201220. The AMP-evoked responses were insensitive to AACOCF3 or ryanodine. They were reduced significantly by 1) U-73122, which is a phospholipase C inhibitor; 2) cyclopiazonic acid, which blocks the Ca(2+) pump in intraneuronal membranes; and 3) 2-aminoethoxy-diphenylborane, which is an inositol (1,4,5)-trisphosphate receptor antagonist. Inhibitors of PKC or calmodulin-dependent protein kinase also suppressed the AMP-evoked excitatory responses. Exposure to AMP suppressed fast nicotinic ionotropic postsynaptic potentials, slow metabotropic excitatory postsynaptic potentials, and slow noradrenergic inhibitory postsynaptic potentials in the submucosal plexus. Inhibition of each form of synaptic transmission reflected action at presynaptic inhibitory adenosine A(1) receptors. Slow excitatory postsynaptic potentials, which were mediated by the release of ATP and stimulation of P2Y(1) purinergic receptors in the submucosal plexus, were not suppressed by AMP. The results suggest an excitatory action of AMP at adenosine A(2A) receptors on neuronal cell bodies and presynaptic inhibitory actions mediated by adenosine A(1) receptors for most forms of neurotransmission in the submucosal plexus, with the exception of slow excitatory purinergic transmission mediated by the P2Y(1) receptor subtype.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Effects of dibutyryl cyclic AMP, ouabain, and xanthine derivatives on crossbridge kinetics in rat cardiac muscle.

In a previous communication, we showed that beta-adrenergic stimulation of cardiac muscles was associated with an increase in the rate of cycling of crossbridges as measured by perturbation analysis in the frequency domain. In this analysis, the frequency at which dynamic stiffness is a minimum (fmin) is taken as a measure of the rate of crossbridge cycling. In this paper, we test the hypothesis that the beta-adrenergic receptor-induced increase in crossbridge cycling rate is mediated by elevation of the intracellular level of cyclic AMP. The approach taken is to compare the effects on fmin in rat papillary muscles during Ba(2+)-activated contractures of 1) an agonist of cyclic AMP that can easily penetrate the cell, namely, dibutyryl cyclic AMP, 2) agents that block cyclic AMP phosphodiesterase, namely, the xanthine derivatives isobutylmethylxanthine and caffeine, and 3) an inotropic agent that does not affect the intracellular level of cyclic AMP, namely, ouabain. Our results showed that dibutyryl cyclic AMP at a dose of 5 mM has the same actions as beta-adrenergic stimulation: it potentiated the isometric twitch force, reduced the time to peak tension and time to half relaxation, and shifted fmin by a factor of 1.8 +/- 0.1 (n = 5). Isobutylmethylxanthine at up to 1.1 mM also acted in the same manner, increasing fmin by a factor of 1.8 +/- 0.2 (n = 6), but ouabain, at a dose (0.03 mM) sufficient to potentiate twitch force by 40 +/- 2% (n = 4), was without effect on the time course of the twitch nor was fmin changed (n = 4). Our findings support the hypothesis that a beta-adrenergic receptor-mediated increase in crossbridge cycling rate is due to an increase in intracellular cyclic AMP level and illustrate the usefulness of the frequency domain analysis approach in the analysis of the mechanism of action of inotropic agents.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Neutral endopeptidase inhibition with inhaled phosphoramidon: no effect on bronchial responsiveness to adenosine 5'-monophosphate (AMP) in asthma.

Part of the contractile response of adenosine in the asthmatic airways may be due to the activation of peptidergic pathways with subsequent local release of spasmogenic neuropeptides. At present, little is known about the potential role of lung peptidases in modulating adenosine-induced airway dysfunction in humans in vivo. We have, therefore, investigated the change in bronchial reactivity to adenosine 5'-monophosphate (AMP), after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double-blind, placebo-controlled, randomized study of 12 asthmatic subjects. Subjects attended on six separate occasions, during which concentration response studies with inhaled AMP and methacholine were carried out, initially in the absence of treatment and then after nebulized phosphoramidon sodium salt (10[-5] M) or matched placebo 5 min prior to a bronchoprovocation test with AMP or methacholine. Agonist responsiveness was expressed as the provocative concentration of AMP or methacholine producing a 20% fall in FEV1 from baseline (PC[20,AMP] or PC[20,meth], respectively). When compared to placebo, phosphoramidon failed to potentiate the airway response to AMP. The geometric mean (range) PC20 AMP value of 23.4 (4.4-190.6) mg x mL(-1) after placebo was not significantly different from that of 20.7 (45-100.9) mg x mL(-1) obtained after phosphoramidon. The lack of change in bronchial reactivity to adenosine 5'-monophosphate after phosphoramidon indicates that endogenous airway neutral endopeptidase may not be of physiological importance in modulating the contractile response of adenosine in the airways. Thus, the present data do not support the view that activation of peptidergic pathways with subsequent local release of spasmogenic neuropeptides is important in the airway response to adenosine

Adenosine Monophosphate↗
PubMed1995

Evidence for the involvement of cyclic AMP in the pheromonal modulation of barnacle settlement

The involvement of cyclic AMP in the settlement of the cypris larva of Balanus amphitrite amphitrite Darwin has been examined through the use of compounds that affect intracellular cyclic AMP levels. The activation of adenylate cyclase with forskolin, and the inhibition of phosphodiesterase with 3-isobutyl-1-methylxanthine, caffeine and theophylline, significantly increased the settlement of cyprids. Although the analogue dibutyryl cyclic AMP appeared to increase settlement, the effect was not significant. No marked increase in settlement resulted from the incubation of cyprids with dibutyryl cyclic GMP, 8-(4-chlorophenylthio) (CPT) cyclic AMP or papaverine (a phosphodiesterase inhibitor). Miconazole nitrate, an adenylate cyclase inhibitor, prevented settlement, but this effect appeared to be physico-chemical rather than pharmacological. Radioimmunoassay did not clearly show whether cyclic AMP levels changed following exposure of cyprids to a pulse of crude barnacle extract. However, exposure to forskolin significantly increased the cyclic AMP titre of cyprids. We conclude that compounds that alter intracellular cyclic AMP levels alter normal patterns of cyprid settlement. Whether this is because of an alteration in signal transduction is unclear.

Journal Article↗
PubMed2003

Different sensitivities of mutants and chimeric forms of human muscle and liver fructose-1,6-bisphosphatases towards AMP.

AMP is an allosteric inhibitor of human muscle and liver fructose-1,6-bisphosphatase (FBPase). Despite strong similarity of the nucleotide binding domains, the muscle enzyme is inhibited by AMP approximately 35 times stronger than liver FBPase: I0.5 for muscle and for liver FBPase are 0.14 microM and 4.8 microM, respectively. Chimeric human muscle (L50M288) and chimeric human liver enzymes (M50L288), in which the N-terminal residues (1-50) were derived from the human liver and human muscle FBPases, respectively, were inhibited by AMP 2-3 times stronger than the wild-type liver enzyme. An amino acid exchange within the N-terminal region of the muscle enzyme towards liver FBPase (Lys20-->Glu) resulted in 13-fold increased I0.5 values compared to the wild-type muscle enzyme. However, the opposite exchanges in the liver enzyme (Glu20-->Lys and double mutation Glu19-->Asp/Glu20-->Lys) did not change the sensitivity for AMP inhibition of the liver mutant (I0.5 value of 4.9 microM). The decrease of sensitivity for AMP of the muscle mutant Lys20-->Glu, as well as the lack of changes in the inhibition by AMP of liver mutants Glu20-->Lys and Glu19-->Asp/Glu20-->Lys, suggest a different mechanism of AMP binding to the muscle and liver enzyme.

Adenosine Monophosphate↗
PubMed1989

Interaction of glyceraldehyde-3-phosphate dehydrogenase with AMP as studied by means of a spin-labeled analog.

The binding of a spin-labeled AMP analog to tetrameric glyceraldehyde-3-phosphate dehydrogenase from rabbit muscle is described. The spin label, perdeuterated and 15N-substituted 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, was attached to C-8 of AMP (C8-SL-AMP). Up to 8 equivalents of C8-SL-AMP bind per enzyme tetramer, i.e., 2 per monomer. Combining sites are the adenine subsite of the coenzyme-binding domain and the phosphate site. Glyceraldehyde 3-phosphate causes a conformational change in the enzyme that brings C8-SL-AMP molecules bound to adjacent R-axis-related subunits closer to one another by 0.2-0.3 nm and allows for spin-spin interaction between the nitroxide radicals. Similar, but less pronounced structural changes take place upon lowering the pH from 8 to 7. Addition of a single equivalent of NAD+ to a complex of the enzyme with 7.6 equivalents of C8-SL-AMP leads to the release of almost 4 C8-SL-AMP molecules. This supports our previous findings that binding of just one NAD+ molecule induces conformational changes in all four subunits.

Adenosine Monophosphate↗
PubMed2002

ADP and AMP induce interleukin-1beta release from microglial cells through activation of ATP-primed P2X7 receptor channels.

P2X(7) is a subtype of ATP-gated channels that is highly expressed in astrocytes, microglia, and other immune cells. Activation of P2X(7) purinoceptors by ATP or 3'-O-(4-benzoyl)-benzoyl ATP (BzATP) induces the formation of cytolytic pores and provokes release of interleukin-1beta from immune cells. We investigated the actions of other endogenous nucleotides on recombinant and microglial P2X(7) receptors using electrophysiology, fluorescence imaging, and interleukin-1beta release measurement. We found that initial application of ADP or AMP to Xenopus oocytes expressing P2X(7) receptors was ineffective. However, when ADP and AMP, but not UTP or adenosine, were applied after a brief exposure to ATP or BzATP, they activated P2X(7) receptors in a dose-dependent manner. Moreover, responses to ADP and AMP were also elicited after exposure to low concentrations of ATP and were recorded several minutes after removal of ATP from the extracellular medium. Whole-cell recordings from mouse microglial cells showed that significant responses to ADP and AMP were elicited only after ATP application. YO-PRO-1 dye uptake imaging revealed that, unlike ATP, prolonged application of ADP or AMP did not cause an opening of large cytolytic pores in mouse microglial cells. Finally, ADP and AMP stimulated the release of interleukin-1beta from ATP-primed mouse and human microglial cells. We conclude that selective sensitization of P2X(7) receptors to ADP and AMP requires priming with ATP. This novel property of P2X(7) leads to activation by ATP metabolites and proinflammatory cytokine release from microglia without cytotoxicity.

Adenosine Diphosphate↗
PubMed1991

An engineered liver glycogen phosphorylase with AMP allosteric activation.

Liver and muscle glycogen phosphorylases, which are products of distinct genes, are both activated by covalent phosphorylation, but in the unphosphorylated (b) state, only the muscle isozyme is efficiently activated by the allosteric activator AMP. The different responsiveness of the phosphorylase isozymes to allosteric ligands is important for the maintenance of tissue and whole body glucose homeostasis. In an attempt to understand the structural determinants of differential sensitivity of the muscle and liver isozymes to AMP, we have developed a bacterial expression system for the liver enzyme, allowing native and engineered proteins to be expressed and characterized. Engineering of the single amino acid substitutions Thr48Pro, Met197Thr and the double mutant Thr48Pro, Met197Thr in liver phosphorylase, and Pro48Thr in muscle phosphorylase, did not qualitatively change the response of the two isozymes to AMP. These sites had previously been implicated in the configuration of the AMP binding site. However, when nine amino acids among the first 48 in liver phosphorylase were replaced with the corresponding muscle phosphorylase residues (L1M2-48L49-846), the engineered liver enzyme was activated by AMP to a higher maximal activity than native liver phosphorylase. Interestingly, the homotropic cooperativity of AMP binding was unchanged in the engineered phosphorylase b protein, and heterotropic cooperativity between the glucose-1-phosphate and AMP sites was only slightly enhanced. The native liver, native muscle and L1M2-48L49-846 phosphorylases were converted to the a form by treatment with purified phosphorylase kinase; the maximal activity of the chimeric a enzyme was greater than the native liver a enzyme and approached that of muscle phosphorylase a. From these results we suggest that tissue-specific phosphorylase isozymes have evolved a complex mechanism in which the N-terminal 48 amino acids modulate intrinsic activity (Vmax), probably by affecting subunit interactions, and other, as yet undefined regions specify the allosteric interactions with ligands and substrates.

Adenosine Monophosphate↗
PubMed1979

[Evaluation of AMP symptoms in independent and self assessment].

11 co-workers (9 physicians, 2 psychologists) of our research department with experience in the use of the AMP system participated in this study. According to the level of observation, 139 AMP symptoms were classified into 3 categories. 44 symptoms were classified into category SB (self-rating), 51 into category FB (psychiatrists' rating) and 44 into category SF (mixed rating). This showed the combination of different levels of observation in the AMP system. The symptoms of the 3 categories show an unequal distribution among the 9 AMP syndromes according to Baumann. The classification of the different symptoms according to the level of observation should be demonstrated during training sessions with the AMP system. This could avoid uncertainties in the judgement of AMP symptoms and improve the inter-rater reliability of the AMP system.

Humans↗
PubMed1980

Dibutyryl cyclic AMP does not influence glomerular collagen or basement membrane production in vitro.

Glomeruli isolated from normal rat renal cortex were incubated for 3 hr with radiolabeled proline in the presence or absence of dibutyryl cyclic AMP. Following incubation, glomerular basement membranes were purified with osmotic lysis followed by selective solubilization of the cell membranes and intracellular proteins with detergents. This technique permitted quantitative recovery of radiolabeled membranes synthesized under different incubational conditions. Dibutyryl cyclic AMP did not affect the incorporation of radioactive precursor glomerular basement membrane (control = 14.72 +/- 1.08 cpm/microgram of membrane protein; cyclic AMP = 14.43 +/- 1.13). Nondialyzable [14C]protein and hydroxy[14C]proline were also measured in the media and in the various glomerular cell fractions obtained during isolation of the basement membranes. Protein ([14C]proline) and collagen (OH[14C]proline) secretion into the media in incubations with cyclic AMP did not differ from that in control incubations. OH[14C]proline content was greatest (congruent to 23% in the water-soluble fraction recovered after osmotic lysis, but significant amounts of OH[14C]proline were also associated with the detergent-solubilized cell fractions. Dibutyryl cyclic AMP had no effect on either glomerular protein or collagen synthesis in these experiments. The results suggest that total glomerular basement membrane production in mixed cell populations is not modulated via a cyclic AMP--coordinated mechanism but do not exclude the possibility that cyclic AMP modulates the amount or kind of collagen synthesis by individual glomerular cell types.

Animals↗
PubMed1981

Relaxation of vascular smooth muscle by isoproterenol, dibutyryl-cyclic AMP and theophylline.

There is evidence that the relaxation of vascular smooth muscle produced by isoproterenol or cyclic AMP is mediated by membrane hyperpolarization. The current study investigates the possibility that this hyperpolarization, and hence the relaxation, may be produced by activation of the electrogenic sodium pump. Rat and pig tail artery strips were placed in a 1.0-mM potassium solution for 15 min. This procedure results in a decrease in the activity of the sodium pump. The strips were then made to contract in response to norepinephrine. Two minutes later, the concentration of potassium was increased to 6.0 mM and a relaxation occurred. The amplitude of this relaxation reflects the activity of the sodium pump. Either isoproterenol or dibutyryl-cyclic AMP causes an enhancement (time or degree) of potassium-induced relaxation. Theophylline potentiated potassium-induced relaxation in pig arteries but not in rat arteries. The relaxant action of isoproterenol on 1.0 mM barium contractures of rat arteries was inhibited by treatment with ouabain or with potassium-free solution. Ouabain inhibited the relaxant action of isoproterenol in pig arteries contracted with depolarizing potassium solution but not in rat tail arteries. Dibutyryl-cyclic AMP, theophylline and nitroprusside caused relaxation of serotonin-induced contractions; however, in rat arteries these responses were not inhibited by ouabain or by the absence of potassium. Similar studies on tail arteries from baboons, dogs, pigs and cats showed that relaxation by dibutyryl-cyclic AMP or by theophylline had some dependency on the activity of the sodium pump. These observations are consistent with the following conclusions: 1) isoproterenol and cyclic AMP potentiate the electrogenic pumping of sodium and potassium responsible for potassium-induced relaxation; 2) the relaxing action of isoproterenol, dibutyryl-cyclic AMP and theophylline are dependent upon experimental conditions and the species from which the vascular tissue is obtained; and 3) there is a component of isoproterenol- and cyclic AMP-induced relaxation which is not altered by inhibition of the electrogenic sodium pump in the rat.

Animals↗
PubMed1984

The structural gene for AMP nucleosidase. Mapping, cloning, and overproduction of the enzyme.

A mutant of Escherichia coli which contained no detectable AMP nucleosidase activity (EC 3.2.2.4) was produced by treatment with nitrosoguanidine and identified by a colorimetric assay for AMP nucleosidase in individual colonies from agar plates. Conjugation experiments indicated a close linkage between the AMP nucleosidase locus (amn) and his. Assays for AMP nucleosidase in E. coli strains with deletions in the his region established that amn is not located between attP2H and mgl . Transduction experiments with bacteriophage P1 were used to construct a linkage map in the his and amn region of the 100-min chromosome map of E. coli, which places amn at 43.3 min. A Rec- strain of E. coli ( FP4102 ) which carries the uvrC to his region (42.1-44.1 min) as an F' episome was used to confirm this location. The episome from FP4102 was used as the source of DNA for cloning amn. BamHI restriction fragments of the episome were inserted into the homologous site of pBR322 and used to transform the Amn- strain of E. coli to Amn+. The transforming plasmid contained a 9-kb (kilobase) insert. Partial restriction of plasmid with ClaI and religation gave a plasmid with a 6-kb insert which retains the amn gene. Restriction mapping of the plasmid has identified ClaI and PstI sites which appear to be within the amn locus. E. coli (Rec-) which contains the 9-kb plasmid of pBR322 containing amn overproduces AMP nucleosidase when grown in the presence of ampicillin. The specific activity of AMP nucleosidase increases from 0.016 mumol/min/mg of protein to 0.32 mumol/min/mg of protein in extracts of the wild type and the plasmid-bearing strains, respectively. A simple purification procedure yields 10 mg of homogeneous AMP nucleosidase from 25 g of packed cells.

Bacteriophage lambda↗
PubMed1984

Effects of allosteric activation on the primary and secondary kinetic isotope effects for three AMP nucleosidases.

Kinetic isotope effects (V/K) were measured with AMP nucleosidases isolated from Azotobacter vinelandii, from a Vmax mutant enzyme of A. vinelandii and from Escherichia coli. Specifically labeled AMP substrates were used to measure 3H secondary and 14C primary kinetic isotope effects on the N-glycosidic bond hydrolysis of AMP in the presence and absence of the allosteric activator, MgATP. Use of the three enzymes, variable MgATP concentration, a poor substrate (dAMP), and variable pH has allowed determination of the isotope effects over a 5000-fold range in the catalytic turnover number. The primary kinetic isotope effects were 1.025 +/- 0.004 and 1.041 +/- 0.006 for the native A. vinelandii enzyme and mutant enzyme, respectively, and were independent of MgATP concentration. The E. coli AMP nucleosidase had a primary isotope effect of 1.019 +/- 0.003 which was also independent of MgATP concentration. The secondary kinetic isotope effect decreased from 1.066 +/- 0.003 to 1.045 +/- 0.002 for the native enzyme from A. vinelandii as the concentration of MgATP increased from 0 to 500 microM. The secondary isotope effect of the mutant enzyme remained constant at 1.088 +/- 0.005 as the MgATP concentration increased from 0 to 500 microM. The secondary isotope effect of the E. coli enzyme showed a similar pattern to that of the native enzyme, decreasing from 1.087 +/- 0.003 to 1.050 +/- 0.003 as the enzyme was saturated with MgATP at a constant concentration of AMP. Saturation with AMP in the absence of MgATP gave similar results and suggested that AMP can cause the allosteric transition. Both the primary and secondary isotope effects for the native enzyme from A. vinelandii remained constant as the pH was varied in the absence of MgATP. Secondary isotope effects with a poor substrate, dAMP, were 1.08 for both the mutant and wild type enzymes from A. vinelandii in the presence of allosteric activator. In the native enzyme, this isotope effect was independent of MgATP concentration. The relative insensitivity in the magnitude of observed isotope effects to pH, allosteric activator, the mutant enzyme, and a poor substrate (dAMP) indicate that intrinsic isotope effects are being expressed. The data are interpreted in terms of a single rate-limiting transition state for hydrolysis of the N-glycosidic bond, although other mechanisms cannot be eliminated. Using this model, the transition states of the native A. vinelandii and E. coli enzymes exhibit properties of both dissociative and associative mechanisms but become more associative as the allosteric activator becomes saturating.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1982

The effect of AMP on inhibition of muscle phosphorylase a by glucose derivatives.

Kinetic studies of the inhibition of rabbit muscle phosphorylase a D-glucan:orthophosphate alpha-D-glucosyltransferase (EC 2.4.1.1) by various glucose derivatives indicate that glucose derivatives in the chair conformation (glucose, 2-deoxyglucose, glucosyl fluoride, and 1-O-methylglucose) stabilize the "T" form of phosphorylase a, whereas those in the half-chair conformation (1,5-gluconolactone and glucal) bind to the "R" form. Derivatives which stabilized the T form were generally competitive inhibitors of phosphate binding, were synergistic with caffeine, and weakened AMP binding. Derivatives which bound to the R form were noncompetitive with respect to Pi in the presence of AMP. The mechanism of inhibition of the R form by gluconolactone and glucal appears to depend upon the presence or absence of AMP. In the presence of the nucleotide, gluconolactone is probably a linear mixed-type inhibitor. However, in the absence of AMP, simple linear uncompetitive inhibition was apparent. Since gluconolactone is thought to be an analogue of the substrate transition state of the phosphorylase reaction, a major function of nucleotide in activating phosphorylase may be the formation of the transition state binding pocket in the binary enzyme-glycogen complex. In the absence of AMP, glucal was competitive with respect to phosphate. However, in the presence of nucleotide, simple intersecting linear noncompetitive inhibition was observed. The results indicate that a second function of AMP is the formation of the phosphate binding pocket in the enzyme-glucal-glycogen-AMP complex. This conclusion is consistent with the crystallographic and structural data available at present.

Adenosine Monophosphate↗
PubMed1995

Liver targeting of adenine arabinoside monophosphate (ara-AMP) by coupling to lactosaminated human serum albumin.

Adenine arabinoside monophosphate (ara-AMP) is a potent antiviral agent against hepadnaviruses but its use in the treatment of chronic hepatitis B is hampered by severe neurotoxic side effects, which are dose dependent. In order to reduce these adverse reactions and to adopt the lysosomotropic approach to antiviral chemotherapy, ara-AMP was coupled to lactosaminated human serum albumin (L-HSA), a neoglycoprotein which specifically penetrates hepatocytes. In mice with Ectromelia virus hepatitis, ara-AMP coupled with L-HSA was selectively delivered to liver cells in which it was released in a pharmacologically active form. Moreover in woodchucks with WHV hepatitis and in patients with chronic HBV infection, coupled ara-AMP inhibited hepadnavirus replication at a dose (1.5 mg/kg/day) 3-6 times lower than the free drug. A clinical study using a 28-day period of treatment with conjugated ara-AMP at 1.5 mg/kg/day has now been started. In the first 6 patients the treatment has been completed. The conjugate inhibited virus growth without producing any side effects. L-HSA-ara-AMP conjugate must be given by intravenous infusion. New hepatotropic conjugates of ara-AMP have been recently prepared which could be administered by bolus intravenous injection or by intramuscular route. These complexes might assure a better compliance in patients with hepatitis B virus infection for a long lasting liver targeted antiviral treatment.

Amino Sugars↗
PubMed1997

Characterization of [3H]AMP binding to rat adipose plasma membranes and its substrate specificity.

We evaluated the binding of [3H]AMP to rat adipose plasma membranes and studied the substrate specificity of the process. The [3H]AMP binding was investigated by high-speed filtration under conditions of virtually complete inhibition of the 5'-nucleotidase activity by EDTA/Na. The Scatchard plot revealed the existence of a single class of AMP-binding sites on the membrane surface with Kd of 2.14 +/- 0.210 microM and the binding capacity (Bmax) of 26.0 +/- 0.68 pmol per mg protein. Addition of ATP (12.5 microM) or ADP (3.5 microM) to the incubation medium resulted in a two-fold increase of Kd, whereas in the presence of adenosine (400 microM) or its pharmacological antagonist theophylline (200 microM), the number of AMP-binding sites decreased. Therefore, ATP and ADP but not adenosine compete with AMP for the same nucleotide-binding site. It is suggested that the observed [3H]AMP binding may be primarily caused by the interaction of AMP with a specific substrate-binding active centre of the membrane ectoenzyme 5'-nucleotidase.

Adenosine↗
PubMed1981

Cyclic AMP level in relation to different conditions of sporulation rhythm regulation in Leptosphaeria michotii (west) Sacc.

When Leptosphaeria michotii was grown in conditions that permitted a stable periodicity of sporulation (asparagine 6.6 mM and in darkness or asparagine 2.6 mM in continuous white light), he level of intracellular cyclic AMP was lower and the activity of the cyclic AMP phosphodiesterase higher in contrast to the cultures with an instable periodicity. With asparagine 6.6 mM and in darkness, theophylline (1 mM) increased the intracellular cyclic AMP level whereas caffeine (1 mM) had no effect. Theophylline (0.01 and 0.1mM) or caffeine (0.01 - 1 mM) provoked a rhythm instability under these conditions. Isoproterenol (1 mM) increased the cyclic AMP level. Nevertheless, the instable rhythm observed in control fed with asparagine 2.6 mM in darkness, was partially stabilized with isoproterenol 0.01 micron or 0.01 - 1 mM. Exogenous cyclic AMP (0.01 - 1 mM) provoked a complete regulation of the rhythm with asparagine 2.6 mM and a shortening of the stable period (from 27 to 21 h) when the fungus was grown on asparagine 6.6 mM. These results underlined the fact that Leptosphaeria rhythm regulation was not dependent on the cyclic AMP level only.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1976

Decreased cyclic AMP and insulin responses to glucose in pancreatic islets of diabetic Chinese hamsters.

The dose as well as the time kinetics of insulin and adenosine-3',5'-monophosphate (cyclic AMP) responses to glucose were compared in pancreatic islets isolated from normal and diabetic Chinese hamsters. The insulin content in diabetic islets was about one-half that in normal islets. Insulin release in diabetic islets incubated for 10 min with glucose 60-1000 mg/100 ml was from one-third to one-half that in normal islets. Glucose 1000 mg/100 ml stimulated three-fold increases in insulin release without increasing the accumulation of [3H] cyclic AMP in either normal or diabetic islets prelabelled with [3H] adenine. However, in the presence of 1.0 mM of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), glucose 150 mg/100 ml elicited significant increases of insulin release (+ 134%) and [3H] cyclic AMP accumulation in islets (+ 44%) and incubation medium (+ 48%) of islets of normal but not diabetic hamsters. Also, in perifusion experiments with 0.1 mM IBMX, glucose 500 mg/100 ml produced threefold greater increases in insulin release and two-fold greater increases in efflux of cyclic AMP in normal than diabetic islets. By contrast with the lesser effects of glucose in diabetic islets, 1.0 mM IBMX increased islet and medium cyclic AMP, as well as insulin release, similarly in normal and diabetic islets. It is suggested that the impairment of glucose-induced insulin release in islets of the diabetic Chinese hamster may be due to a defective interaction of glucose with the adenylate cyclase-cyclic AMP system in the pancreatic B cell.

3',5'-Cyclic-AMP Phosphodiesterases↗