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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mouse spleen-derived mast cell line (PT-18) was employed to examine the mechanisms of adenosine 3':5'-monophosphate (cAMP)-mediated inhibition of antigen-induced lipid mediator biosynthesis. Specifically, we tested the hypothesis that increasing cAMP in mast cells inhibits lipid mediator biosynthesis by a mechanism independent of effects on histamine release (degranulation) or changes in cytosolic calcium concentration. Forskolin inhibited antigen-induced prostaglandin D2 (PGD2), leukotriene C4 (LTC4), and leukotriene B4 (LTB4) production by 30-50%. In contrast, forskolin had no inhibitory effect on antigen-induced increases in cytosolic calcium concentration, as monitored by the calcium indicator fura-2, or histamine release from the cells. The combination of the phosphodiesterase inhibitor isobutylmethylxanthine with forskolin inhibited the antigen-induced production of PGD2 and LTC4 by 90-100% and histamine release by about 60%. These responses were accompanied by a virtual abolition of the antigen-induced increase in cytosolic calcium. To test further the hypothesis that increasing cAMP can lead to inhibition of lipid mediator biosynthesis in the absence of effects on cytosolic calcium, we employed the calcium ionophores A23187 and ionomycin. Forskolin alone or in combination with isobutylmethylxanthine had no effect on ionophore-induced increases in cytosolic calcium but effectively inhibited leukotriene biosynthesis. In addition, increasing cyclic AMP led to an inhibition of ionophore-induced production of platelet-activating factor and liberation of arachidonic acid. These data suggest that a relatively modest increase in cAMP-dependent protein kinase activity in mast cells leads to inhibition of the lipase-catalyzed cleavage of arachidonic acid from membrane phospholipids in the absence of measurable effects on either histamine release or changes in cytosolic calcium concentration. This effect results in a selective inhibition of the biosynthesis of lipid mediators including LTC4, LTB4, PGD2, and platelet-activating factor.
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PMID:Inhibition by adenosine 3':5'-monophosphate of eicosanoid and platelet-activating factor biosynthesis in the mouse PT-18 mast cell. 169 Nov 75

Endocochlear potential (EP) and cochlear microphonics (CM) were recorded during the perilymphatic perfusion with forskolin known as an adenylate cyclase stimulant. Forskolin produced a reversible EP elevation in a dose-dependent manner. Perfusion with 1,9-dideoxy-forskolin, an analogue of forskolin that does not stimulate adenylate cyclase, had no effect on EP, whereas perfusions with other agents that raise the cAMP-level (IBMX, a phosphodiesterase inhibitor, and dbcAMP) duplicated the effect of forskolin. The vigorous CM during the EP elevation and the large negative EP induced by anoxia superimposed on the elevated EP indicate that the K+ diffusion potential through the hair cell membrane cannot be altered by forskolin. The results suggest that the adenylate cyclase system in the stria vascularis and/or Reissner's membrane may modulate the generation of EP.
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PMID:Effects of forskolin and 1,9-dideoxy-forskolin on cochlear potentials. 169 40

1. Isolated coiled reabsorptive sweat ducts from normal subjects and patients with cystic fibrosis (CF) were cultured in vitro. Cells were harvested and plated onto permeable supports to form confluent cell sheets. The Ussing chamber technique was used to study pharmacological regulation of the transepithelial ion transport in these membranes. 2. Addition of a stable cyclic AMP analogue, 8-Br-cyclic AMP, to normal cell cultures resulted in a decrease of the transepithelial potential difference (PD). 3. Forskolin exposure resulted in a similar PD decrease, which was augmented by the phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX). 4. Exposure to isoprenaline, prostaglandin E2 (PGE2), and phenylephrine resulted in a response mimicking the forskolin-induced response, that was also amplified by IBMX. 5. Pre-incubation with cholera toxin abolished the isoprenaline response and reduced the control resistance. 6. Propranolol abolished the responses induced by isoprenaline and phenylephrine, whereas phentolamine had no effect. PGE2-induced responses were inert to both types of blockers. 7. Indomethazine addition to an unstimulated membrane resulted in a weak PD increase, i.e. a response opposite to that induced by isoprenaline. 8. IBMX addition to an unstimulated membrane resulted in a weak isoprenaline-like response. When the cells were pre-treated with indomethazine this IBMX response was absent. 9. Unidirectional Cl- isotope flux studies demonstrated a large increase of net Cl- reabsorption in response to isoprenaline and PGE2. 10. Mannitol isotope flux studies revealed that the paracellular permeability was unaffected by isoprenaline exposure. 11. Membranes derived from CF patients did not respond similarly to any of these agents. However, a weak spike, occasionally followed by a gradual increase of the short-circuit current (Iscc), was observed in both normal subjects and CF patients. 12. It is concluded that the primary effect on ion transport of factors increasing the cyclic AMP in normal cultured sweat duct cells is an activation of a transcellular Cl- permeability. This effect was missing in cells derived from CF patients.
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PMID:Chloride permeability regulation via a cyclic AMP pathway in cultured human sweat duct cells. 169 99

Forskolin, a diterpene derivative of the Indian plant Coleus forskhohlii, proved to be a marked positive inotropic and vasodilatory compound in animal experiments with a mechanism of action distinct from catecholamines, cardiac glycosides, and phosphodiesterase-inhibiting compounds. The cardiovascular effects of forskolin seem to be mediated by a direct stimulatory action at the catalytic unit of sarcolemmal adenylate cyclase. The aim of the present study was to clarify the cardiovascular profile of this compound in 12 patients with stage III (NYHA) congestive cardiomyopathy. The effects of forskolin were investigated by invasive techniques using the thermodilution catheter method and compared to the beta 1-receptor agonist dobutamine and the vasodilator sodium nitroprusside in an intraindividual comparison. Forskolin dose-dependently reduced cardiac pre- and afterload values, and led to a reduction in systolic, diastolic, and mean pulmonary artery pressure as well as pulmonary wedge pressure by greater than 50% concomitant with an increase in cardiac output. There was a slight increase in heart rate. Cardiac stroke volume and stroke volume index was increased by approximately 70%. The cardiovascular effects of dobutamine and nitroprusside were less pronounced; however, it seemed that a similar hemodynamic profile could be achieved by the combination of both dobutamine and sodium nitroprusside. In view of the rapid development of tolerance toward beta 1-receptor stimulation, forskolin, with its receptor-independent mechanism of action, may be advantageous for the treatment of severe heart failure, especially in patients with catecholamine-insensitive heart failure.
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PMID:Cardiovascular effects of forskolin (HL 362) in patients with idiopathic congestive cardiomyopathy--a comparative study with dobutamine and sodium nitroprusside. 169 72

To investigate the role of cyclic adenosine-3'5'-monophosphate on the inhibitory actions of opioids in guinea-pig ileum, we made intracellular recordings from the two electrophysiologically defined classes of neurons (S and AH) in the myenteric plexus. The selective opioid mu agonist (D-Ala2,N-Me-Phe4,Gly5-ol)-enkephalin caused a membrane hyperpolarization in 34 out of 67 S neurons but did not affect the membrane potential of AH neurons. The mean amplitude (+/- S.E.M.) of the hyperpolarization was 8.2 +/- 0.8 mV. Forskolin, which activates adenylate cyclase and increases intracellular cyclic adenosine-3',5'-monophosphate levels, caused a membrane depolarization in AH neurons (9.4 +/- 1.9 mV) but did not alter the resting membrane potential of S neurons. Similarly, neither the phosphodiesterase inhibitor, isobutylmethylxanthine, nor the membrane permeable analogue of cyclic adenosine-3',5'-monophosphate, dibutyryl cyclic adenosine-3'-5'-monophosphate, altered the resting membrane properties of S neurons. Furthermore, none of these agents affected significantly the amplitude of the hyperpolarization of S neurons by (D-Ala2,N-Me-Phe4,Gly5-ol)-enkephalin. The experiments indicate that changes in intracellular cyclic adenosine-3',5'-monophosphate are not important in the processes that link occupation of mu receptors to the opening of potassium channels on myenteric neurons.
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PMID:Hyperpolarization of myenteric neurons by opioids does not involve cyclic adenosine-3',5'-monophosphate. 169 62

Cyclic AMP appears to be involved in several excitatory actions of amines on neurones of the Limulus cardiac ganglion. Amines selectively increase levels of cardiac ganglion cyclic AMP with a magnitude and time course similar to that observed for amine-induced excitation of cardiac ganglion burst rate. With respect to either the physiological or biochemical effect, the apparent order of potency is octopamine greater than epinephrine approximately dopamine greater than norepinephrine. Elevation of cardiac ganglion cyclic AMP levels by octopamine or dopamine is dose-dependent and is potentiated by the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (IBMX). Several pharmacological agents which influence cyclic nucleotide metabolism, including forskolin, IBMX and 8-substituted cyclic AMP analogues, have amine-like effects on the Limulus cardiac ganglion. These effects include increased burst rate of the isolated cardiac ganglion and decreased burst duration, interburst interval and number of spikes per burst in follower neurones. Forskolin and IBMX increase levels of cardiac ganglion cyclic AMP, and IBMX also increases cyclic GMP levels in this tissue. Amines, forskolin and IBMX have direct effects on follower neurones pharmacologically isolated from pacemaker cell input. Octopamine, forskolin and IBMX depolarize follower neurones, while dopamine hyperpolarizes these cells. Amines, forskolin and IBMX elicit burst-like potentials in follower neurones, and increase the size of evoked, unitary junction potentials recorded in cardiac muscle fibres. These pharmacological and biochemical data suggest that multiple, excitatory effects of biogenic amines on the Limulus cardiac ganglion are mediated by simultaneous increases in cyclic AMP at several loci within this neural network.
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PMID:Involvement of cyclic AMP in multiple, excitatory actions of biogenic amines on the cardiac ganglion of the horseshoe crab Limulus polyphemus. 170 51

Enzymatically dissociated ganglia from the myenteric plexus of the guinea-pig small intestine were used to investigate changes in levels of cyclic 3',5'-adenosine monophosphate (cAMP) in response to stimulation of adenylate cyclase by forskolin and inhibition of phosphodiesterase by 3-isobutyl-1-methylxanthine (IBMX). A linear relation with a positive correlation coefficient greater than 0.98 was found between: (1) amount of cAMP and number of ganglia; (2) amount of protein and number of ganglia; (3) amount of DNA and amount of protein; (4) amount of DNA and number of ganglia. Basal levels of cAMP were 2.25 +/- 0.21 fmol per ganglion for 900 ganglia. Forskolin stimulated a dose-dependent increase in cAMP over a concentration range of 0.05 to 50 microM, with a level of 18.6 +/- 4.9 fmol/ganglion at 50 microM forskolin. The inactive forskolin analog 1,9-dideoxyforskolin did not elevate cAMP. Addition of IBMX to the incubation medium stimulated a dose-dependent increase in cAMP over a concentration range of 0.1-1000 microM, with a level of 17.58 +/- 3.38 fmol/ganglion at 1000 microM IBMX. Application of 1 mM IBMX strongly potentiated the stimulating action of forskolin on cAMP levels. Our results derived from direct determination of cAMP changes in small intestinal myenteric ganglia are consistent with existing electrophysiological evidence for second messenger function of cAMP in slow synaptic modulation of excitability in AH/Type 2 neurons of the enteric nervous system.
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PMID:Determination of levels of cyclic AMP in the myenteric plexus of guinea-pig small intestine. 171 66

We have determined the effect of forskolin, an adenyl cyclase agonist, and 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, on the accumulation and cytotoxicity of cisplatin (DDP) in 2008 human ovarian carcinoma cells. In DDP-sensitive 2008 cells, forskolin and IBMX caused 2.1-fold and 2.3-fold increases, respectively, in the short-term accumulation of DDP relative to untreated cells. The inactive analogue, 1,9-dideoxyforskolin, decreased DDP accumulation. Forskolin and IBMX also increased accumulation in A2780 cells. Neither forskolin nor IBMX had any effect on DDP accumulation in DDP-resistant 2008 cells. The effects were detectable as early as 1 min and persisted at 60 min. The concentrations for half-maximal stimulation of DDP accumulation were approximately 0.2 microM for forskolin and 0.2 mM for IBMX. Forskolin caused marked increases in cAMP levels in both sensitive and resistant 2008 cells within 1 min, although there were differences in the subsequent time-courses of the response. Both 2008 cell types had identical cAMP-dependent protein kinase (PKA) activity. These results suggest that there is a target downstream of PKA that is an important participant in DDP accumulation, and that this target is defective or missing in DDP-resistant cells. Following a 1-hr exposure to drugs, forskolin and IBMX at concentrations that were by themselves completely non-toxic increased the slopes of the clonogenic survival vs. DDP concentration curves in 2008 cells 1.9-fold and 3.3-fold, respectively. In DDP-resistant 2008 cells, however, forskolin and IBMX increased the slopes only 1.2 and 2.6-fold, respectively. These effects of forskolin and IBMX on DDP cytotoxicity did not directly correlate with the effects on the 1-hr DDP accumulation which suggested that, in addition to modulating DDP accumulation, these agents increase the cytotoxicity of the intracellular platinum. The results indicate that modulation of cAMP levels can have important effects on DDP accumulation and cytotoxicity in 2008 cells and that these effects are significantly diminished in DDP-resistant cells.
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PMID:Modulation of cis-diamminedichloroplatinum(II) accumulation and sensitivity by forskolin and 3-isobutyl-1-methylxanthine in sensitive and resistant human ovarian carcinoma cells. 171 75

Recent evidence has suggested that cAMP plays a role as a second messenger in the decrease in nociceptive threshold (or hyperalgesia) produced by agents acting on primary afferent terminals. In support of this hypothesis we report that intradermal injection of a direct activator of adenyl cyclase, forskolin, produces a dose-dependent hyperalgesia in the rat. The duration of this hyperalgesia was prolonged by the phosphodiesterase inhibitors, isobutylmethylxanthine and rolipram. Forskolin hyperalgesia was antagonized by the Rp isomer of cyclic adenosine-3'5'-monophosphothioate, an analog of cAMP that prevents the phosphorylation of the cAMP protein kinase. The Rp isomer of cyclic adenosine-3'5'-monophosphothioate also inhibited the hyperalgesia induced by a membrane-permeable analogue of cAMP, 8-bromocyclic adenosine monophosphate, as well as the hyperalgesia induced by agents that are presumed to act directly on primary afferent nociceptors: prostaglandin E2, prostaglandin I2, (8R,15S)-dihydroxyicosa(5E-9,11,13Z)tetraenoic acid; and the adenosine A2-agonist 2-phenylaminoadenosine. Although the cAMP second messenger system contributes to primary afferent hyperalgesia, we found no evidence for a contribution of protein kinase C. Thus, hyperalgesia induced by prostaglandin E2, prostacyclin (prostaglandin I2), (8R,15S)-dihydroxyicosa(5E-9,11,13Z)tetraenoic acid, the adenosine A2-agonist 2-phenylaminoadenosine, 8-bromocyclic adenosine monophosphate and the direct activator of adenyl cyclase, forskolin, were not significantly attenuated by the selective inhibition of protein kinase C by the 19-31 fragment of protein kinase C. Two other inhibitors of protein kinase C, sphingosine and staurosporine, also failed to attenuate prostaglandin E2-induced hyperalgesia.
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PMID:Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia. 172 88

Brefeldin A (BFA) causes rapid redistribution of Golgi proteins into the ER, leaving no definable Golgi apparatus, and blocks transport of proteins into post-Golgi compartments in the cell. In this study we follow the disassembly of the Golgi apparatus in BFA-treated, living cells labeled with NBD-ceramide and demonstrate that forskolin can both inhibit and reverse this process. Long, tubular processes labeled with NBD-ceramide were observed emerging from Golgi elements and extending out to the cell periphery in cells treated with BFA for 5 min. With longer incubations in BFA, the NBD label was dispersed in a fine reticular pattern characteristic of the ER. Treatment with forskolin inhibited these effects of BFA as well as BFA's earliest morphologic effect on the Golgi apparatus: the redistribution to the cytosol of a 110-kD Golgi peripheral membrane protein. In addition, forskolin could reverse BFA's block in protein secretion. Forskolin inhibition of BFA's effects was dose dependent and reversible. High concentrations of BFA could overcome forskolin's inhibitory effect, suggesting forskolin and BFA interact in a competitive fashion. Remarkably, in cells already exposed to BFA, forskolin could reverse BFA's effects causing the 110-kD Golgi peripheral membrane protein to reassociate with Golgi membrane and juxtanuclear Golgi complexes to reassemble. Neither membrane permeant cAMP analogues nor cAMP phosphodiesterase inhibitors could replicate or enhance forskolin's inhibition of BFA. 1,9-Dideoxyforskolin, which does not activate adenylyl cyclase, was equally as effective as forskolin in antagonizing BFA. A derivative of forskolin, 7-HPP-forskolin, that is less potent than forskolin at binding to adenylyl cyclase, was also equally effective as forskolin in antagonizing BFA. In contrast a similar derivative, 6-HPP-forskolin, that is equipotent with forskolin at binding to adenylyl cyclase, did not inhibit BFA's effects. These results suggest that forskolin acts as a competitive antagonist to BFA, using a cAMP-independent mechanism to prevent and reverse the morphologic effects induced by BFA.
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PMID:Forskolin inhibits and reverses the effects of brefeldin A on Golgi morphology by a cAMP-independent mechanism. 184 46


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