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PubMed1980

Induction of surface glycoprotein expression by cyclic AMP in Chinese hamster ovary cells.

Surface expression of a membrane glycoprotein of 135,000 molecular weight (P135) was inducible by adenosine 3',5' -cyclic monophosphate in Chinese hamster ovary cells, CHO-K1 clone. Cells were cultured in the presence or absence of cyclic AMP derivatives, chemicals influencing cytoplasmic cyclic AMP levels, or inhibitors of protein or RNA synthesis. Surface proteins wre radiolabeled by a lactoperoxidase-catalyzed iodination reaction and analyzed by two-dimensional polyacrylamide gel electrophoresis. Surface expression of P135 increased 3---5-fold inthe presence of N6,O2' -dibutyryl cyclic AMP or 8-parachlorophenylthio cyclic AMP. Induction was also observed after treatment with prostaglandins E1 and F2 alpha, but not with sodium butyrate. Phosphodiesterase inhibitor, Roche compound Ro20-1724, enhanced the effect of N6,O2' -dibutyryl cyclic AMP. Metabolic incorporation of [35S]methionine into P135 was increased by N6,O2' -dibutyryl cyclic AMP. The induction was sensitive to inhibitors of protein and RNA biosynthesis. These results are consistent with a proposal that cyclic AMP controls the synthesis of this protein. Metabolic incorporation of a radioactive precursor suggested that P135 was a glucos-amine-containing glycoprotein. P135 appeared to be strongly associated with cell membrane because it was resistant to extraction of plasma membrane by cole 0.1 N NaOH.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1980

Low molecular weight cyclic AMP binding protein isolated from the extract of human tonsillar lymphocytes.

A protein fraction of molecular weight 33,000-36,000 accounted for about 40% of the cyclic AMP binding capacity of the cytoplasmic extract of human tonsillar lymphocytes. This cyclic AMP binding fraction (designated as R' protein [10]) proved to be a proteolytic fragment of the regulatory subunit of the cyclic AMP-dependent protein kinase. The Scatchard plot of cyclic AMP binding by the isolated R' fraction indicated positive cooperativity. 50% saturation of the cyclic AMP binding sites was achieved at about 4 . 10(-9) M cyclic AMP. An upward concave curve was obtained in the Scatchard plot of cyclic GMP binding by the R' protein. These results strongly suggest that more than one molecule of cyclic nucleotide can be bound by one molecule of the R' protein. The R' protein could not be detected in the physiological salt extract of isolated nuclei in which type I cyclic AMP-dependent protein kinase was the dominating isoenzyme (according to the terminology used by Corbin, S.D., Keely, S.L. and Park, C.R. (1975) J. Biol. Chem. 250, 218-225). The cytoplasm of cells contained a higher amount of type II than type I regulatory subunit. In the cytoplasm the predominant part of RII was present in the dissociated state in all preparations, while when the RII was found in the nucleus it was mainly in the holoenzyme form. The R' protein presumably from the dissociated type II regulatory subunit.

Carrier Proteins↗
PubMed1981

Aminopyrine uptake by guinea pig gastric mucosal cells. Mediation by cyclic AMP and interactions among secretagogues.

The role of cyclic nucleotides in regulating acid secretion by dispersed mucosal cells from guinea-pig stomach was examined by measuring first the ability of histamine and carbachol to stimulate [dimethylamine-14C]aminopyrine uptake and cyclic nucleotide metabolism and secondly, the effect of exogenous cyclic nucleotides on basal and stimulated [14C]aminopyrine uptake. The [14C]aminopyrine was found in an acidic, osmotically sensitive compartment, probably associated with the initial steps in acid secretion by these cells. Although histamine increased [14C]aminopyrine uptake and cyclic AMP synthesis as expected, histamine was approx. 10-fold more potent in inducing [14C]aminopyrine uptake. This dissociation of [14C]aminopyrine uptake and cyclic AMP metabolism process was further manifested by the observation that prostaglandin E1 failed to increase [14C]aminopyrine uptake, although it did cause a rise in cellular cyclic AMP. Furthermore, prostaglandin E1 did not alter the [14C]-aminopyrine uptake caused by histamine. Carbachol was found to increase the [14C]aminopyrine uptake and also to potentiate the ability of histamine to increase [14C]aminopyrine uptake. Carbachol, however, affected neither the histamine-induced increase in cyclic AMP nor the binding of [3H]histamine to the cells. Cimetidine, a histamine H2 receptor antagonist, blocked the [14C]aminopyrine uptake induced either by histamine alone or by the potentiating combination of histamine plus carbachol. These results suggest that cyclic AMP is mediating the action of histamine on [14C]aminopyrine uptake but changes in cyclic AMP per se are not necessarily the cause for the potentiated increase in [14C]aminopyrine uptake. Furthermore, the potentiated response observed with histamine plus carbachol on [14C]aminopyrine uptake occurs at a biochemical step distal to and not obviously related to cyclic AMP generation.

Aminopyrine↗
PubMed1992

P2 purinoceptor-mediated cyclic AMP accumulation in bovine vascular smooth muscle cells.

Extracellular ATP has been shown to induce intracellular Ca2+ mobilization and adenylate cyclase inhibition via P2 purinoceptors in several species of cells. Now we found that in calf vascular smooth muscle cells the addition of ATP to the medium did not induce inhibition but stimulation of cyclic AMP accumulation, in addition to stimulation of inositol phosphate production. Adenosine and AMP also induced cyclic AMP accumulation but their efficacy was much less than that of ATP. The ATP action was not influenced by the presence of either adenosine deaminase or of an ATP regenerating system, whereas the AMP action was increased by the regenerating system. The results indicate that the cyclic AMP accumulation by ATP is due to ATP itself but neither to adenosine nor to AMP, both of which are produced from ATP. ATP receptor coupled to the cyclic AMP generation was shown to be different from that coupled to phospholipase C based on the difference in the potency order of the receptor agonists and in the sensitivity of P2 receptor agonists to 8-cyclopentyl-1,3-dipropylxanthine (CPX)- and suramin-induced antagonism. We conclude that in the aortic smooth muscle cells a novel P2-type receptor directly coupled to adenylate cyclase activation exists in addition to the previously known P2 receptor linked to phospholipase C activation.

Adenosine Triphosphate↗
PubMed1995

Radioimmunoassays for cyclic AMP cross-react with phosphodiesterase inhibitors and buffer components.

We addressed the issue of cross-reactivity of several commonly used phosphodiesterase inhibitors with radioimmunoassays for cyclic AMP, after we had observed a considerably high cross-reactivity with a noncommercial antibody. Theophylline, pentoxifylline, penthydroxifylline (BL 194), albifylline (HWA 138), torbafylline (HWA 448), A 80 2715, isobutyl methylxanthine, and the nonmethylxanthines amrinone and rolipram were dissolved in supplemented and boiled cell culture medium (RPMI 1640). These samples were assayed for apparent cyclic AMP in two different, commercially available radioimmunoassay kits (based on polyclonal antibodies), applying the nonacetylated protocol. Cross-reactivity was dose-dependent and nonlinear. Samples containing theophylline and amrinone exhibited the strongest cross-reactivity in assay A (NEN/DuPont): 3.0 +/- 0.5(-nM) and 2.4 +/- 1.1 (-nM) apparent cyclic AMP +/- SD at 1-nM spike, respectively. With the more sensitive assay B (Amersham), higher concentrations of apparent cyclic AMP were detected: from 7.9 +/- 0.4 nM (for albifylline) to 3.5 +/- 0.1 nM (for rolipram). Values were calculated from standard curves set up in the respective assay buffer, where culture medium controls resulted in 1.8 +/- 0.3 nM and 3.1 +/- 0.1 nM for assay A and B, respectively. The culture medium interference increased with rising cyclic AMP concentrations. Although comparatively low, this degree of cross-reactivity is relevant for in vitro experiments. Phosphodiesterase inhibitors are commonly administered at millimolar concentrations, and resulting cyclic AMP levels are often in the nanomolar range. Neglecting these findings may lead to falsely high readouts of cyclic AMP concentrations.

Buffers↗
PubMed2004

A calpain-like proteolytic activity produces the limited cleavage at the N-terminal regulatory domain of rabbit skeletal muscle AMP deaminase: evidence of a protective molecular mechanism.

On storage at 4 degrees C, rabbit skeletal muscle AMP deaminase undergoes limited proteolysis with the conversion of the native 85-kDa enzyme subunit to a 75-kDa core that is resistant to further proteolysis. Further studies have shown that limited proteolysis of AMP deaminase with trypsin, removing the 95-residue N-terminal fragment, converts the native enzyme to a species that exhibits hyperbolic kinetics even at low K+ concentration. The results of this report show that a 21-residue synthetic peptide, when incubated with the purified enzyme, is cleaved with a specificity identical to that reported for ubiquitous calpains. In addition, the cleavage of a specific fluorogenic peptide substrate by rabbit m-calpain is inhibited by a synthetic peptide that corresponds to residues 10-17 of rabbit skeletal muscle AMP deaminase; this peptide contains a sequence (K-E-L-D-D-A) that is present in the fourth subdomain A of rabbit calpastatin, suggesting that the N-terminus of AMP deaminase shares with calpastatin a regulatory sequence that might exert a protective role against the fragmentation-induced activation of AMP deaminase. These observations suggest that a calpain-like proteinase present in muscle removes from AMP deaminase a domain that holds the enzyme in an inactive conformation and which also contains a regulatory region that protects against unregulated proteolysis. We conclude that proteolysis of AMP deaminase is the basis of the large ammonia accumulation that occurs in skeletal muscle subjected to strong tetanic contraction or passing into rigor mortis.

AMP Deaminase↗
PubMed1999

Phosphodiesterase 4-dependent regulation of cyclic AMP levels and leukotriene B4 biosynthesis in human polymorphonuclear leukocytes.

Several selective phosphodiesterase 4 inhibitors were found to be potent inhibitors of the N-formyl-Met-Leu-Phe (fMLP)-induced leukotriene B4 biosynthesis by human polymorphonuclear leukocytes with IC50s in the nanomolar range (0.09-26 nM). The rank order of potency was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (RS-14203) > 3-benzyl-5-phenyl-3H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (KF18280) > 8-aza-1-(3-nitrophenyl)-3-(4-pyridylmethyl)-2,4-quinazoline dione (RS-25344) > 3-cyclo-pentyloxy-N-[3,5-dichloro-4-pyridyl]-4-methoxybenzamide (RP-73401) > R-rolipram > R-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl] pyridine (CDP840)> S-rolipram. Isoproterenol (IC50 = 350 nM) and prostaglandin E2 (IC50 = 59 nM) also suppressed leukotriene B4 biosynthesis. Inhibitors of the phosphodiesterase 1 (8-methoxymethyl-1-methyl-3-(2-methylpropyl)xanthine (8-MeOMe-IBMX)), phosphodiesterase 2 (erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA)), phosphodiesterase 3 (quazinone and milrinone) and phosphodiesterase 5 (zaprinast and dipyridamole) had no inhibitory effects on the fMLP-induced leukotriene B4 biosynthesis (IC50s > 20 microM). All phosphodiesterase 4 inhibitors caused an accumulation of cellular cyclic AMP to 140-185% over the basal level of fMLP-treated control cells, comparable to that observed with high concentrations of isoproterenol and prostaglandin E2. In contrast, the complete inhibition of leukotriene B4 production by 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) inhibitors had no effect on cyclic AMP levels. Phosphodiesterase 1, 2, 3 and 5 inhibitors had little effect on the level of cellular cyclic AMP (89-126% of the basal cyclic AMP level). Dose-dependencies for R-rolipram, RS-14203 and CDP840 indicated that the maximal accumulation of cyclic AMP occurred at concentrations of phosphodiesterase 4 inhibitors higher than those required for the inhibition of leukotriene B4 production. The presence of a mixture of 8-MeOMe-IBMX, EHNA, milrinone and zaprinast to inhibit phosphodiesterase 1, 2, 3 and 5 had little effect on the dose-dependence of R-rolipram for the inhibition of leukotriene B4 biosynthesis or cyclic AMP accumulation. These data demonstrate that selective phosphodiesterase 4 inhibitors can inhibit the fMLP-induced leukotriene B4 biosynthesis in human polymorphonuclear leukocytes with a potency similar or greater than that of potent 5-lipoxygenase or FLAP inhibitors. This inhibition is accompanied by small variations in the levels of cellular cyclic AMP and appears to proceed independently of the other phosphodiesterases.

Cyclic AMP↗
PubMed1999

Effects of NKH477 on renal functions and cyclic AMP production in anesthetized dogs.

The present study was undertaken to evaluate the effects of an adenylate cyclase activator N,N-dimethyl-beta-alanine[3R-(3alpha, 4alphabeta, 5beta, 6beta, 6aalpha, 10alpha, 10abeta, 10balpha)]-5(acetyloxy)-3-ethenyldodecahydro-10, 10b-dihydroxy-3, 4a, 7, 7, 10a-pentamethyl-1-oxo-1H-naphtho [2,1-b] pyran-6-yl ester hydrochloride (NKH477) on renal functions and cyclic AMP production in the dog kidney. The intrarenal arterial infusion of NKH477 (30, 100 and 300 ng kg(-1) min(-1)) increased renal blood flow, glomerular filtration rate, urine flow rate, urinary Na+ and cyclic AMP excretion, fractional Na+ excretion and arterial and renal venous plasma cyclic AMP concentrations in a dose-dependent manner. The intrarenal arterial infusion of rolipram (0.3 microg kg(-1) min(-1)), a cyclic AMP-specific phosphodiesterase inhibitor, also caused the same renal responses as NKH477. The increasing effects of NKH477 on renal blood flow, fractional Na+ excretion and renal venous plasma cyclic AMP concentration were facilitated in the presence of rolipram. NKH477 reduced glomerular filtration rate and filtration fraction in the presence of rolipram. The increasing effects of NKH477 on urine flow rate and urinary Na+ excretion were not affected by rolipram. The present results suggest that NKH477 increases glomerular filtration and suppresses tubular sodium reabsorption through activation of cyclic AMP production, and thereby induces natriuresis. The results also demonstrate that renal cyclic AMP level during the activation of adenylate cyclase is regulated by phosphodiesterase IV in both the vascular and tubular sites.

Anesthesia↗
PubMed2001

Effects of short- and long-term exposure to c-AMP and c-GMP on the noradrenaline transporter.

The effects of short- and long-term exposure of cells to elevated cyclic adenosine monophosphate (c-AMP), using dibutyryl-c-AMP, 8-bromo-c-AMP, cholera toxin or forskolin, or cyclic guanosine monophosphate (c-GMP), using dibutyryl-c-GMP or 8-bromo-c-GMP, on the activity and expression of the noradrenaline transporter (NAT) were examined. Short- or long-term c-GMP elevation had no effects on (3)H-noradrenaline uptake by rat PC12 phaeochromocytoma cells or human SK-N-SH-SY5Y neuroblastoma cells. Short-term c-AMP elevation (for 17 min experiment duration) caused a decrease in (3)H-noradrenaline uptake by PC12 cells, but had no effects on SK-N-SH-SY5Y cells or COS-7 cells transfected with human or rat NAT cDNA. c-AMP did not affect (3)H-nisoxetine binding to PC12 cells. Long-term (24 h) exposure to elevated c-AMP levels caused a decrease in (3)H-noradrenaline uptake and NAT mRNA in PC12 cells, but had no effects on SK-N-SH-SY5Y cells and caused a small increase in (3)H-noradrenaline uptake in COS-7 cells heterologously expressing rat or human NAT. Hence, c-AMP, but not c-GMP, causes a cell type-dependent reduction in NAT activity after short-term exposure and a reduction in NAT expression after long-term exposure.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMedDate not supplied

Cyclic AMP potentiation of cytokine-induced nitric oxide synthase activity in a murine astrocyte cell line.

Astrocytes in culture have been previously shown to express inducible nitric oxide synthase (iNOS) following treatment with cytokines such as interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma). We report here on the effects of the cyclic nucleotide analogues 8-bromo-cyclic AMP and 8-bromo-cyclic GMP on cytokine-stimulated iNOS gene expression in a cultured murine astrocyte cell line. In these cells, neither 8-bromo-cyclic AMP nor 8-bromo-cyclic GMP alone was able to stimulate iNOS activity. Similarly, neither IL-1 beta nor IFN-gamma was capable of independently stimulating iNOS expression. Co-stimulation with both cytokines, however, resulted in measurable increases in iNOS activity, and correlated to increases in iNOS mRNA levels. The addition of 8-bromo-cyclic AMP, but not 8-bromo-cyclic GMP, was found to further enhance the expression of iNOS activity induced by IL-1 beta and IFN-gamma co-stimulation. This potentiation effect of 8-bromo-cyclic AMP correlated to a further elevation in iNOS mRNA levels over that produced by cytokine co-stimulation alone. However, 8-bromo-cyclic AMP co-treatment with either cytokine alone did not stimulate iNOS activity, indicating that the signal transduction pathway(s) involved in the potentiation effect of 8-bromo-cyclic AMP is functional only in the presence of both cytokines. These results indicate that cyclic AMP-mediated processes can participate in modulating the expression of astrocyte iNOS when the appropriate combinations of stimulatory cytokines are present.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Melatonin inhibits pituitary adenylyl cyclase-activating polypeptide-induced increase of cyclic AMP accumulation and [Ca2+]i in cultured cells of neonatal rat pituitary.

The effects of melatonin on pituitary adenylyl cyclase-activating polypeptide-induced increase of cyclic AMP and [Ca2+]i were studied in neonatal rat pituitary cells. The polypeptide increased cyclic AMP accumulation. In the presence of melatonin the increase of cyclic AMP was inhibited in a dose-dependent manner, the maximal inhibition was achieved with 1-10 nM melatonin. Pituitary adenylyl cyclase-activating polypeptide also increased [Ca2+]i in 30% of the pituitary cells and melatonin inhibited the effect. Most of the cells sensitive to adenylyl cyclase-activating polypeptide (77%) were also sensitive to GnRH, suggesting they are gonadotrophs. The remaining cells were not identified. The polypeptide-induced [Ca2+]i increase was inhibited in Ca2+-free medium in 2/3 of the cells indicating that Ca2+ influx was involved. To examine causal relationship between cyclic AMP and [Ca2+]i increase, we have studied the effect of adenylyl cyclase activation by forskolin on intracellular Ca2+ concentration. Forskolin had similar effects as adenylyl cyclase-activating polypeptide: it increased [Ca2+]i in the pituitary cells and the increase was dependent on presence of Ca2+ in the medium. Melatonin inhibited the forskolin induced [Ca2+]i increase. Our observations indicate that increase of cyclic AMP stimulates Ca2+ influx in the pituitary cells of neonatal rat and that this mechanism is involved in [Ca2+]i increase induced by the pituitary adenylyl cyclase-activating polypeptide. Because melatonin inhibits increase of cyclic AMP induced by pituitary adenylyl cyclase-activating polypeptide or forskolin, the inhibitory effect of melatonin on Ca2+-influx may be mediated by the decrease of cyclic AMP concentration. This mechanism of melatonin action has not been described previously. Because melatonin inhibits the polypeptide- or forskolin-induced [Ca2+]i also in the cells not sensitive to GnRH, melatonin receptors seem to be present on both gonadotrophs and non-gonadotrophic pituitary cells.

Animals↗
PubMed1997

Inhibition of stimulated cyclic AMP production by multiple neuropeptide Y receptors in the rat brainstem.

Neuropeptide Y (NPY) has been shown to modulate blood pressure, heart rate and to inhibit the baroreceptor reflex at the level of nucleus tractus solitarius (NTS). The aim of this study was to examine effects of NPY and its related peptides on forskolin (1 microM)-stimulated cyclic AMP production in slices of the rat NTS. Each peptide was present at 0.3 microM. Pretreatment with NPY inhibited the stimulated increase in cyclic AMP levels in slices of rat NTS. Also [Pro34]NPY, an analog, which activates Y1, Y3 (and Y5) receptors inhibited the stimulated increase in cyclic AMP levels. However, pretreatment with the Y1 receptor-selective antagonist BIBP3226 (3 microM) did not affect the [Pro34]NPY-evoked inhibition of cyclic AMP levels. In addition, [Leu31,Pro34]NPY, an Y1 (and PP1/Y4 and Y5) receptor agonist did not inhibit the stimulated increase in cyclic AMP production. Also the Y2 receptor-selective agonist C2-NPY inhibited the stimulated elevation of cyclic AMP levels, while peptide YY, which does not recognize Y3 receptors did not significantly affect the stimulated cyclic AMP production. In conclusion, it seems that Y2 and Y3 receptors are coupled to inhibition of adenylate cyclase activity in the rat NTS.

Animals↗
PubMed2000

Activated phosphorylation of cyclic AMP response element binding protein is associated with preservation of striatal neurons after focal cerebral ischemia in the rat.

Phosphorylation of the DNA-binding transcription factor, cyclic AMP response element binding protein, has recently been suggested to provide neuroprotective signals in times of cellular stress. Medium-sized striatal neurons are among the cells that are most vulnerable to ischemic stress in the brain. In the present study, phosphorylation of cyclic AMP response element binding protein was immunohistochemically evaluated in rat striatum in order to examine the ischemic vulnerability of each striatal region from the standpoint of cyclic AMP response element binding protein. Rats were subjected to 90-min focal cerebral ischemia followed by various periods of recirculation. Focal ischemia was induced by occlusion of the middle cerebral artery by the intraluminal suture method. Local cerebral blood flow measured by the 14C-iodoantipyrine method in the lateral and the medial striatal regions during occlusion was 5.0+/-7. 1 and 42.5+/-8.1ml/100g/min, respectively. Cerebral blood flow in each region was restored to the control level during the recirculation period. The lateral and the medial regions of the striatum in the sham animals showed hardly any immunoreactivity with the specific antibody against phosphorylated cyclic AMP response element binding protein. By contrast, at 3.5h of recirculation, a number of phosphorylated cyclic AMP response element binding protein-positive neurons were detected in the medial striatal region on the occluded side, and the increase in the number of immunopositive cells continued until two weeks of recirculation with gradual decline. The lateral striatal region on the ischemic side showed only a mild increase in phosphorylated cyclic AMP response element binding protein-positive cells at 3.5h of recirculation, and the immunoreactivity rapidly disappeared during the subsequent recirculation period. Appreciable increase in immunoreactive cells was also noted in the contralateral striatum during the early phase of recirculation, and this increase seemed to be associated with spontaneous circling movements of the animals. Cresyl Violet staining revealed that striatal neurons in the medial region remained intact until two weeks of recirculation, whereas neurons in the lateral striatal region soon showed ischemic damage, followed by complete neuronal loss, and evolution of a frank infarct. Immunoreactivity for bcl-2, apoptosis-suppressive protein, was clearly detected in many neurons in the medial striatal region, but no such immunoreactivity was detected in the lateral striatal region. These findings suggest that persistently activated phosphorylation of cyclic AMP response element binding protein in the striatum during post-ischemic recirculation may be closely associated with protection of striatal neurons on the ischemic side, while it may be associated with spontaneous circling movements on the contralateral side.

Animals↗
PubMed1999

Phosphorylation of transcription factor cyclic-AMP response element binding protein mediates c-fos induction elicited by sustained hypertension in rat nucleus tractus solitarii.

We investigated the role of cyclic-AMP response element binding protein signaling in the induction of the immediate-early gene c-fos by baroreceptor activation in neurons of the nucleus tractus solitarii of anesthetized rats. Activation of the arterial baroreceptors with sustained hypertension significantly increased the number of neurons in the caudal nucleus tractus solitarii that were immunoreactive to an antiserum that detects Ser133-phosphorylated cyclic-AMP response element binding protein. This implied increase in phosphorylation of cyclic-AMP response element binding protein was subsequently followed by an elevation in the expression of Fos protein in neurons of the nucleus tractus solitarii. Microinjection bilaterally into the nucleus tractus solitarii of a phosphorothioated antisense oligonucleotide directed against the initiation site of cyclic-AMP response element binding protein messenger RNA discernibly reduced the manifested immunoreactivity of phosphorylated cyclic-AMP response element binding protein in response to baroreceptor activation. This was accompanied by a decline in the transcription of c-fos messenger RNA and the expression of Fos protein, along with an appreciable potentiation of the baroreceptor reflex response. Control injections of the sense oligonucleotide or artificial cerebrospinal fluid were ineffective. These findings suggest that phosphorylation of cyclic-AMP response element binding protein is crucial to Fos expression in the nucleus tractus solitarii elicited by sustained hypertension. As such, phosphorylation of cyclic-AMP response element binding protein may be an important early nuclear event that mediates the long-term inhibitory modulation of the baroreceptor reflex response by Fos protein at the nucleus tractus solitarii.

Animals↗
PubMed1990

Dopamine and its agonists reduce a light-sensitive pool of cyclic AMP in mouse photoreceptors.

The exposure to bright light of dark-adapted (DKA) mouse retinas incubated in the dark (DI) in IBMX-containing medium causes a marked loss of cyclic AMP. This light response also occurs if the medium contains 10 mM aspartate or cobaltous ion, agents believed to confine the effects of light to photoreceptors. Thus, the action of light in the presence of either of these agents defines a light-sensitive pool of cyclic AMP in photoreceptors. This pool could also be reduced or eliminated in DKA-DI retinas by nanomolar to micromolar levels of dopamine (if the medium contained SCH23390, a potent antagonist of D1 receptors), thus indicating an agonistic action of dopamine at D2 receptors. The D2 agonists LY171555 (EC50 10 nM) or (+)-3-PPP also reduced the cyclic AMP level in the dark. Of the D2 antagonists tested, the butyrophenone spiperone (in the presence of the 5HT-2 blocker ketanserin) countered the action of the D2 agonists but substituted benzamides were ineffective. Consistently, the D2 agonists had no effect on cyclic AMP levels of mutant retinas lacking photoreceptors (rd/rd), but reduced cyclic AMP in DKA-DI glutamate-modified retinas which exhibit a major loss of inner retinal neurons without apparent loss of photoreceptors. The D1 antagonist SCH23390 only reduced cyclic AMP levels of DKA-DI retinas when cyclic AMP levels had been elevated by adding dopamine to the incubation medium.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Human liver AMP-deaminase--oligomeric forms of the enzyme.

AMP-deaminase (EC 3.5.4.6) is a key enzyme of nucleotide breakdown involved in regulation of adenine nucleotide pool in the liver. Mechanisms regulating activity of the enzyme are not completely elucidated, till now. In this paper experimental data indicating on the potential regulatory significance of changes in oligomeric structure of the enzyme are presented. SDS-PAG electrophoresis of human liver AMP-deaminase revealed the presence of three enzyme fragments. Only largest of them (the protein fragments weighing 68 kDa) reacted immunologically with anti- (human liver) AMP-deaminase antibodies. At physiological pH 7.0, in the absence of regulatory ligands, reaction catalysed by human liver AMP-deaminase was strongly dependent on enzyme concentration used, with half-saturation constant (S0.5) values increasing significantly with the degree of enzyme dilution. Preincubation with activated long-chain fatty acids--substances promoting dissociation of oligomeric enzymes, inhibited the activity of AMP-deaminase studied nearly completely. Gel filtration on Sepharose CL-6B column demonstrated existence of at least three active oligomeric forms of human liver AMP-deaminase. We postulate that oligomeric structure of the enzyme is a factor determining regulatory profile of AMP-deaminase studied.

AMP Deaminase↗
PubMed1995

Alterations in cyclic AMP generation and G protein subunits following transient ischemia in gerbil hippocampus.

We examined alterations in the cyclic AMP generating system and G protein subunits in gerbil hippocampus following 10 min of transient ischemia. In hippocampal slices, basal and isoproterenol- and forskolin-stimulated cyclic AMP accumulations were markedly increased at 6 and 24 h after ischemia. Interestingly, both the inhibition of forskolin-stimulated cyclic AMP and the potentiation of beta-adrenoceptor-stimulated cyclic AMP by a gamma-aminobutyric acidB receptor agonist were attenuated at these time points. Ischemia did not affect the immunolabeling of any of the G protein alpha subunits; only that of beta subunits was significantly decreased, by 28.2%, 4 days after ischemia. In contrast, pertussis toxin-catalyzed [32P]ADP ribosylation declined progressively during the late recirculation period, reaching a significant reduction (25.4%) at 6 h after ischemia. These results suggest that ischemia affects the heterotrimeric conformation (alpha beta gamma) of Gi/Go during the recirculation period, thereby leading to increased cyclic AMP production. Because cyclic AMP-dependent protein kinase A modulates the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-kainate receptor channels, postischemic sensitization of the cyclic AMP generating system may contribute to neuronal degeneration in the hippocampus.

Adenosine Diphosphate Ribose↗
PubMed1998

Role of cyclo-oxygenase-2 induction in interleukin-1beta induced attenuation of cultured human airway smooth muscle cell cyclic AMP generation in response to isoprenaline.

Airway smooth muscle (ASM) in human asthma shows reduced relaxation and cyclic AMP generation in response to beta-adrenoceptor agonists. IL-beta attenuates cyclic AMP generation but the underlying mechanism is unclear. We have reported that IL-1beta induces cyclo-oxygenase-2 (COX-2) in human ASM cells and results in a marked increase in prostanoid generation with PGE2 and PGI2 as the major products. We investigated the role of COX-2 induction and prostanoid release (measured as PGE2) in IL-1beta induced attenuation of cyclic AMP generation in response to the beta-adrenoceptor agonist isoprenaline (ISO). Pre-treatment of human ASM cells with IL-1beta significantly attenuated cyclic AMP generation in response to high concentrations of ISO (1.0-10.0 microM) in a time- and concentration-dependent manner. The effect was accompanied by a high concentration of PGE2 release. The non-selective COX inhibitor indomethacin (Ind), the selective COX-2 inhibitor NS-398, the protein synthesis inhibitors cycloheximide (CHX) and actinomycin D and the steroid dexamethasone (Dex) all abolished the PGE2 release and prevented the attenuated cyclic AMP generation. COX substrate arachidonic acid time- and concentration-dependently mimicked IL-1beta induced attenuation and the effect was prevented by the non-selective COX inhibitors Ind and flurbiprofen, but not by NS-398, CHX and Dex. In contrast to IL-1beta, TNFalpha and IFNgamma, which are ineffective in inducing COX-2 and releasing PGE2 from human ASM cells, did not affect the cyclic AMP formation. Our study demonstrates that COX-2 induction and the consequent release of prostanoids plays a crucial role in IL-1beta induced attenuation of human ASM cell cyclic AMP response to ISO.

Adrenergic beta-Agonists↗