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

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

The effect of increased intracellular cAMP on MCF-7 breast cancer cell growth was examined by treating cells with either forskolin, an activator of adenylate cyclase, or 8-[4-chlorophenylthio]-cAMP (8-CPT-cAMP), a cAMP analog. Compared to cells maintained in control medium, treatment with either 1 or 10 microM forskolin decreased cell growth by 17% and 68%, respectively, whereas treatment with 250 microM 8-CPT-cAMP decreased cell growth by 29%. To determine whether this effect of cAMP on cell growth was mediated by inhibition of the activity of extracellular signal-regulated kinases 1 and 2 (ERK1 and -2), two mitogen-activated protein kinases, the effect of cAMP on growth factor-induced ERK activity in MCF-7 cells was examined. Treatment with either insulin-like growth factor I (IGF-I) or epidermal growth factor (EGF) for 10 min stimulated a 4- to 8-fold increase in ERK1 and -2 activity. This effect of IGF-I and EGF was not inhibited by increased intracellular cAMP generated by pretreatment of the cells with 10 microM forskolin. Similarly, 10 microM forskolin had no effect on IGF-I- or EGF-induced ERK activity in cells treated with growth factor for 30 min. To determine whether cAMP inhibits other growth factor-mediated effects, its effect on the activity of the serum response element (SRE), a DNA promoter element whose activity is regulated by a variety of growth-promoting events, was examined. For these assays, MCF-7 cells were transiently transfected with pTK81-SRE-Luc, a luciferase fusion gene that contains the SRE cloned 5' to a minimal thymidine kinase promoter and the luciferase gene. Treatment with either IGF-I or EGF increased pTK81-SRE-Luc activity in a dose-dependent fashion. Pretreatment of cells with 10 microM forskolin decreased IGF-I- and EGF-stimulated luciferase activity by approximately 75%. An intermediate effect was observed using 1 microM forskolin. When intracellular cAMP levels were increased using 8-CPT-cAMP, similar results were obtained. SRE activity is dependent upon the activation by phosphorylation of a ternary complex factor; included among the ternary complex factors is Elk-1. When MCF-7 cells were cotransfected with a vector that expresses a Gal4/Elk-1 fusion protein and UAS-TK-Luc, a plasmid that contains two Gal4 DNA recognition sites cloned 5' to a thymidine kinase promoter and the luciferase gene, treatment with forskolin partially inhibited the activation of Elk-1 by IGF-I and EGF. These data demonstrate that in MCF-7 breast cancer cells, cAMP has no effect on IGF-I- or EGF-induced ERK activity, but it inhibits growth factor-induced transcription. Taken together with the effects of cAMP on IGF-I- and EGF-induced Elk-1 activation, these data suggest that the effect of cAMP on SRE activity occurs distal to ERK activation, possibly via inhibition of an ERK-independent pathway. Finally, these data indicate that the effect of increased intracellular cAMP on breast cancer growth may be mediated through inhibition of specific growth factor-induced effects, including gene transcription.
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PMID:Growth factor-induced transcription via the serum response element is inhibited by cyclic adenosine 3',5'-monophosphate in MCF-7 breast cancer cells. 916 3

In gustatory transduction, adenosine 3',5'-cyclic monophosphate (cAMP) has been suggested to close potassium channels when elevated by sweet stimuli or to open cAMP-gated cation channels when depressed by bitter stimuli. These experiments examine the effect of cAMP on whole cell currents from posterior taste receptor cells with standard patch-clamp techniques. Elevating cytosolic cAMP by pipette administration, membrane-permeant analogs [8-(4-chlorophenylthio)-cAMP (CPT-cAMP) and dibutyryl-cAMP], or by phosphodiesterase inhibition [3-isobutyl-1-methylxanthine (IBMX)] produced poorly reversible inhibitions of outward potassium currents by up to 33%. Unexpectedly, middle to high concentrations of forskolin (> 5 microM) profoundly and reversibly inhibited these currents (95%) with greatly accelerated inactivation kinetics. 1,9-Dideoxyforskolin, an ineffective activator of adenylate cyclase, was similarly potent. Kinase inhibitors effectively blocked the effects of cAMP elevations produced by IBMX or CPT-cAMP but did not block these forskolin actions. However, at low concentrations (5 microM), forskolin reduced potassium currents in a phosphorylation-dependent manner. Collectively, these data suggest that cAMP produces a phosphorylation-dependent inhibition of outward potassium currents but that forskolin's actions are independent of cAMP or phosphorylation except at low concentration. cAMP was also effective in altering the waveform of the gustatory action potential, implying it may modify transmission of gustatory information to the brain.
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PMID:cAMP and forskolin inhibit potassium currents in rat taste receptor cells by different mechanisms. 922 30

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.
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PMID:Evidence for the involvement of cyclic AMP in the pheromonal modulation of barnacle settlement 931 89

1. The patch-clamp technique was used in conjunction with the fluorescent Ca2+ indicator indo-1 to measure simultaneously cytosolic Ca2+ concentration ([Ca2+]i) and membrane potential in single rat corticotrophs identified with the reverse haemolytic plaque assay. 2. Application of the adrenocorticotropin (ACTH) secretagogue, corticotropin-releasing hormone (CRH), triggered a sustained [Ca2+]i elevation and membrane depolarization. 3. The CRH action was mediated via the cAMP-dependent protein kinase cascade. Both the CRH-induced depolarization and [Ca2+]i elevation could be mimicked by extracellular application of the adenylate cyclase activator forskolin or the membrane-permeable cAMP analogue, 8-(4-chlorophenylthio)-adenosine-3',5'-cyclic monophosphate (8-CPT-cAMP). Intracellular adenosine cyclic 3',5'-(Rp)-phosphothioate (Rp-cAMPS), a protein kinase A inhibitor, abolished the CRH effects. 4. Voltage-clamp studies suggest that the CRH-triggered depolarization was due to the reduction of background K+ conductances. The CRH-sensitive current was Ca2+ independent and was insensitive to the K+ channel blockers tetraethylammonium (TEA) or 4-aminopyridine (4-AP), but could be partially inhibited by Ba2+. 5. The CRH-triggered steady-state depolarization stimulated extracellular Ca2+ entry via voltage-gated Ca2+ channels and raised [Ca2+]i. CRH failed to stimulate [Ca2+]i rise in cells that were voltage clamped at their resting potential. Removal of extracellular Ca2+ or inhibition of Ca2+ channels by Ni2+ abolished the [Ca2+]i rise. 6. Voltage-clamp studies of voltage-gated Ca2+ channels using Ba2+ as charge carrier show that approximately 90% of the channels were available for activation at the resting potential. CRH did not enhance the voltage-gated Ca2+ channels.
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PMID:Mechanism underlying corticotropin-releasing hormone (CRH) triggered cytosolic Ca2+ rise in identified rat corticotrophs. 936 11

Elevation of cAMP concurrently enhances cholesterol efflux and binding of HDL3 in human skin fibroblasts. These effects were observed regardless of the route by which cAMP levels were increased. Cholesterol efflux and HDL3 binding were stimulated by the cAMP analogue CPT-cAMP, the adenylate cyclase activator forskolin, and by iloprost and prostaglandin E1 (PGE1) (which elevate cAMP via receptor-mediated processes). Dideoxyforskolin and PGF2alpha, which do not elevate cAMP, altered neither cholesterol efflux nor binding of HDL3. Inhibition of protein kinase A with H89 abolished the stimulatory effects of CPT-cAMP and iloprost, suggesting protein kinase A involvement in enhancing cholesterol efflux and HDL3 binding. Enhancement of HDL3 binding by iloprost was due to increased maximal capacity of the cells to bind HDL3, i.e., a greater number of HDL3 binding sites. A positive correlation was demonstrated between changes in HDL3 binding and changes in [3H]cholesterol efflux. The data are compatible with a model in which cholesterol efflux is partially dependent upon HDL binding to the cells. A short exposure to iloprost was sufficient to stimulate cAMP synthesis, triggering a chain of events leading to increased HDL3 binding and [3H]cholesterol efflux 20-24 h later. We conclude that both cholesterol efflux and the maximal capacity for HDL3 binding are enhanced by elevation of cellular cAMP. Cyclic AMP-elevating prostanoids could initiate these responses in vivo.
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PMID:Elevation of cyclic AMP by iloprost and prostaglandin E1 increases cholesterol efflux and the binding capacity for high-density lipoproteins in human fibroblasts. 955 75

Incubating 3T3-L1 adipocytes with forskolin, which increases intracellular cAMP by activating adenylate cyclase, mimicked rapamycin by attenuating the effect of insulin on stimulating the phosphorylation of four (S/T)P sites in PHAS-I, a downstream target of the mammalian target of rapamycin (mTOR) signaling pathway. To investigate the hypothesis that increasing cAMP inhibits mTOR, the protein kinase activity of mTOR was measured in an immune complex assay with recombinant PHAS-I as substrate. Both forskolin and 8-(4-chlorophenylthio)adenosine 3'-5'-monophosphate (CPT-cAMP) prevented the activation of mTOR by insulin in adipocytes, but neither agent affected mTOR activity when added directly to the immunopurified protein. In contrast, the cAMP phosphodiesterase inhibitor, theophylline, inhibited mTOR activity not only when added to intact adipocytes but also when added to immunopurified mTOR in vitro, demonstrating that certain methylxanthines are able to inhibit mTOR independently of increasing cAMP. Forskolin and CPT-cAMP blocked the effect of insulin on increasing mTOR phosphorylation, which was assessed using mTAb1, an antibody whose binding is inhibited by phosphorylation of mTOR. Although the mTAb1 epitope contains a consensus site for protein kinase B, neither agent inhibited the activation of protein kinase B produced by insulin. These findings support the interpretation that increasing cAMP attenuates the effects of insulin on PHAS-I, p70(S6K), and other downstream targets of the mTOR signaling pathway by inhibiting the phosphorylation and activation of mTOR.
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PMID:Attenuation of mammalian target of rapamycin activity by increased cAMP in 3T3-L1 adipocytes. 985 18

The circadian oscillator in Xenopus retinal photoreceptor layers can be reset in similar ways by light and agonists of D2-like dopamine receptors. Treatments that increase cyclic AMP levels act on this oscillator in an opposite fashion, mimicking darkness in the induction of phase shifts. Light and dopamine have each been reported to inhibit adenylate cyclase in photoreceptors. Together, these data suggest that the transduction pathways for entrainment by dopamine and/or light include suppression of cyclic AMP or a cyclic AMP-sensitive step. In these studies, we examined this hypothesis by measuring the effects of treatment with a cyclic AMP analogue on the phase shifts induced in photoreceptor melatonin rhythms by light or a D2 receptor agonist (quinpirole). When photoreceptor layers were treated simultaneously with 8-(4-chlorophenylthio)cyclic AMP (8-CPT-cAMP) and quinpirole at any of three different phases of the circadian cycle, the resulting phase shifts of the melatonin rhythm were always the same as those caused by 8-CPT-cAMP alone. This indicates that there is a cyclic AMP-sensitive step in the dopamine entrainment pathway. In contrast, light pulses did reset the oscillator in the presence of elevated cyclic AMP. This suggests a separate cyclic AMP-insensitive transduction pathway for entrainment by light. Quinpirole reduced basal levels of cyclic AMP in photoreceptors, but light did not. These data suggest that cyclic AMP plays a role in the entrainment pathway activated by dopamine but not in the entrainment pathway activated by light.
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PMID:A role for cyclic AMP in entrainment of the circadian oscillator in Xenopus retinal photoreceptors by dopamine but not by light. 1021 57

We examined the effects of activation of metabotropic glutamate receptors (mGluRs) on glutamatergic synaptic transmission at the neuromuscular junction of newly hatched Drosophila larvae. In nominally Ca(2+)-free solutions puff-application of low concentrations of glutamate evoked a transient frequency increase of miniature synaptic currents (mSCs). The mean amplitude of mSCs was unaffected, suggesting that this effect was presynaptic. Similar alterations of the mSC frequency were obtained using the mGluR agonists, (S)-4C3HPG, DCG-IV, or (1S,3S)-ACPD, but not when using agonists for ionotropic glutamate receptors, NMDA, AMPA or kainate. An mGluR antagonist, MCCG-I, blocked the effect of agonists on the mSC frequency. An adenylate cyclase activator, forskolin, and a cAMP analog, CPT-cAMP, mimicked the effects of mGluR activation. Meanwhile, an adenylate cyclase inhibitor, SQ22,536, blocked the mGluR agonist-induced effects, and in rutabaga, an adenylate-cyclase-defective mutant, the effect of the agonist was greatly reduced. In the presence of external Ca2+, (S)-4C3HPG decreased the failure rate and increased the mean amplitude of stimulus-evoked SCs, while MCCG-I decreased the amplitudes. We suggest that at the larval Drosophila neuromuscular junction endogenous glutamate released at the terminal potentiates synaptic transmission via a process involving cAMP.
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PMID:Activation of metabotropic glutamate receptors enhances synaptic transmission at the Drosophila neuromuscular junction. 1034 Mar 2

Alpha1-adrenoceptor agonists may potentiate relaxation to beta-adrenoceptor agonists, although the mechanisms are unclear. We compared relaxations induced by beta-adrenoceptor agonists and cyclic AMP-dependent vasodilators in rat pulmonary arteries constricted with prostaglandin F2alpha (PGF2alpha) or the alpha1-adrenoceptor agonist phenylephrine (PE). In addition, we examined whether differences were related to cyclic AMP- or nitric oxide (NO) and cyclic GMP-dependent pathways. Isoprenaline-induced relaxation was substantially potentiated in arteries constricted with PE compared with PGF2alpha. Methoxamine was similar to PE, whereas there was no difference between PGF2alpha and 30 mM KCl. The potentiation was primarily due to a marked increase in the NO-independent component of relaxation, from 9.1+/-1.7% for PGF2alpha to 55.1+/-4.4% for PE. NO-dependent relaxation was also enhanced, but to a lesser extent (50%). Relaxation to salbutamol was almost entirely NO-dependent in both groups, and was potentiated approximately 50% by PE. Relaxation to forskolin (activator of adenylate cyclase) was also enhanced in PE constricted arteries. Part of this relaxation was NO-dependent, but the major effect of PE was to increase the NO-independent component. Propranolol diminished but did not abolish the potentiation. There was no difference in response to CPT cyclic AMP (membrane permeant analogue) between PE and PGF2alpha, suggesting that mechanisms distal to the production of cyclic AMP were unchanged. Relaxation to sodium nitroprusside (SNP) was the same for PE and PGF2alpha, although relaxation to acetylcholine (ACh) was slightly depressed. This implies that potentiation by PE does not involve the cyclic GMP pathway directly. Mesenteric arteries constricted with PE did not show potentiation of isoprenaline-induced relaxation compared to those constricted with PGF2alpha, suggesting that this effect may be specific to the pulmonary circulation. These results clearly show that PE potentiates both the NO-independent and -dependent components of cyclic AMP-mediated relaxation in pulmonary arteries of the rat, although the effect on the former is more profound. We suggest that potentiation of both components is largely due to direct activation of adenylate cyclase via alpha1-adrenoceptors, within the smooth muscle and endothelial cells respectively.
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PMID:Potentiation of cyclic AMP-mediated vasorelaxation by phenylephrine in pulmonary arteries of the rat. 1036 85

The vasodilator effects of pituitary adenylate cyclase activating polypeptide (PACAP-27) are subject to tachyphylaxis in rats treated with the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). This study examined whether this tachyphylaxis is due to the loss of vasodilator potency of cAMP generated by activation of the G(s) protein-coupled PACAP receptors. Five successive treatments with PACAP-27 (2 nmol/kg iv) produced pronounced vasodilator responses in saline-treated rats that were not subject to tachyphylaxis. The first injection of PACAP-27 (2 nmol/kg iv) in L-NAME (50 micromol/kg iv)-treated rats produced vasodilator responses of similar magnitude to those in saline-treated rats, whereas four subsequent injections produced progressively and markedly smaller responses. The hemodynamic effects of the membrane-permeable cAMP analog 8-(4-chlorophenylthiol)-cAMP (8-CPT-cAMP; 5-15 micromol/kg iv) were similar in L-NAME-treated rats and in L-NAME-treated rats that had received the five injections of PACAP-27. In addition, five injections of 8-CPT-cAMP (10 micromol/kg iv) produced pronounced vasodilator responses in saline- and L-NAME-treated rats that were not subject to the development of tachyphylaxis. These results suggest that a loss of biological potency of cAMP is not responsible for tachyphylaxis to PACAP-27 in L-NAME-treated rats. This tachyphylaxis may be due to the inability of the G(s) protein-coupled PACAP receptor to activate adenylate cyclase.
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PMID:Tachyphylaxis to PACAP-27 after inhibition of NO synthesis: a loss of adenylate cyclase activation. 1056 19


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