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)

We have been investigating the mechanisms of diurnal and circadian regulation of teleost retinomotor movements. In the retinas of lower vertebrates, photoreceptors and melanin pigment granules of the retinal pigment epithelium (RPE) undergo movements at dawn and dusk. These movements continue to occur at subjective dawn and dusk in animals maintained in constant darkness. Cone myoids contract at dawn and elongate at dusk; RPE pigment disperses into the epithelial cells' long apical processes at dawn and aggregates into the cell bodies at dusk. We report here that forskolin, an adenylate cyclase activator, and 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, each induces dark-adaptive cone and RPE retinomotor movements in isolated light-adapted green sunfish retinas cultured in constant light. Forskolin induces a 22-fold elevation in retinal cyclic AMP content. Forskolin- and IBMX-induced movements are inhibited approximately 65% and 95%, respectively, by 3,4-dihydroxyphenylethylamine (dopamine). However, dopamine does not inhibit dark-adaptive movements induced by dibutyryl cyclic AMP. Epinephrine is much less effective than dopamine in inhibiting forskolin-induced movements, while phenylephrine and clonidine are totally ineffective. These results are consistent with our previous findings that treatments that increase intracellular cyclic AMP content promote dark-adaptive retinomotor movement. They further suggest that dopamine inhibits adenylate cyclase activity in photoreceptors and RPE cells and thereby favors light-adaptive retinomotor movements.
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PMID:Dopamine inhibits forskolin- and 3-isobutyl-1-methylxanthine-induced dark-adaptive retinomotor movements in isolated teleost retinas. 258 Sep 51

Forskolin, a direct activator of adenylate cyclase, stimulates cAMP production in islet cells. The effects of forskolin on the release of somatostatin, glucagon, and insulin were studied using the isolated, perfused dog pancreas. It was found that concentrations ranging from 0.075 microM-1 microM stimulated the secretion of somatostatin, glucagon, and insulin in a dose-related manner. The effects of 0.15 microM and of 0.6 microM forskolin were modulated by the prevailing glucose level with higher D and B and lower A cell responses at high (11 mM) than at low (2.8 mM) or zero glucose. In the absence of extracellular Ca++, forskolin (1 microM) possessed no stimulatory effect on pancreatic hormone secretion. Perfusion of 1 microM atropine, 1 microM propranolol, and 1 microM phentolamine had no effect on forskolin-mediated (0.3 microM) hormone output from pancreas. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (25 microM) elicited qualitatively similar hormone response to forskolin. In conclusion, the experiments demonstrate that forskolin is a potent, reversible, stimulus of pancreatic hormone secretion. Its effects are apparently not mediated via the sympathetic or parasympathetic nerve endings in pancreas. Forskolin may prove to be a valuable pharmacological tool in probing the role of the adenylate cyclase-cAMP system in pancreatic hormone secretion.
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PMID:Forskolin, an activator of adenylate cyclase, stimulates pancreatic insulin, glucagon, and somatostatin release in the dog: studies in vitro. 258 71

The nicotinic acetylcholine receptor (AcChoR) from rat myotubes prelabeled in culture with [32P]orthophosphate was isolated by acetylcholine affinity chromatography followed by immunoaffinity chromatography. Under basal conditions, the nicotinic AcChoR was shown to be phosphorylated in situ on the beta and delta subunits. Regulation of AcChoR phosphorylation by cAMP-dependent protein kinase was explored by the addition of forskolin or cAMP analogues to prelabeled cell cultures. Forskolin, an activator of adenylate cyclase, stimulated the phosphorylation of the delta subunit 20-fold over basal phosphorylation and induced phosphorylation of the alpha subunit. The effect of forskolin was dose dependent with a half-maximal response at 8 microM in the presence of 35 microM Ro 20-1724, a phosphodiesterase inhibitor. Stimulation of delta subunit phosphorylation was almost maximal within 5 min, whereas stimulation of alpha subunit phosphorylation was not maximal until 45 min after forskolin treatment. Stimulation of AcChoR phosphorylation by 8-benzylthioadenosine 3',5'-cyclic monophosphate was identical to that obtained by forskolin. Two-dimensional thermolytic phosphopeptide maps of the delta subunit revealed a single major phosphopeptide. These results correlate closely with the observed effects of forskolin on AcChoR desensitization in muscle and suggest that cAMP-dependent phosphorylation of the delta subunit increases the rate of AcChoR desensitization in rat myotubes.
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PMID:Regulation of nicotinic acetylcholine receptor phosphorylation in rat myotubes by forskolin and cAMP. 281 83

Stimulation-evoked tritium overflow was examined in superfused rat brain cortex slices (stimulus: electrical impulses; 3 Hz) and synaptosomes (stimulus: potassium 12 mmol/l) preincubated with 3H-5-HT. 1. In slices and synaptosomes, the evoked 3H overflow was facilitated by forskolin and 8-Br-cAMP, but was not affected by AH 21-132 (an inhibitor of cAMP phosphodiesterase; cis-6-(p-acetamidophenyl)-1,2,3,4,4a,10b-hexahydro-8,9-dimethoxy-2-methylbenzo [c] [1,6]-naphthyridine). In the presence of AH 21-132, the facilitatory effect of forskolin on evoked overflow was increased. 2. In slices, AH 21-132 or combined administration of forskolin plus AH 21-132 did not change the percentage of basal or evoked 3H overflow represented by unmetabolized 3H-serotonin (about 30% and 60%, respectively). 3. In slices, cocaine or 6-nitroquipazine, an inhibitor of serotonin uptake, did not influence the increase in evoked overflow produced by forskolin plus AH-21-132. Forskolin plus AH 21-132 did not alter the inhibitory effect of serotonin (examined in the presence of 6-nitroquipazine) and the facilitatory effect of metitepin (a serotonin receptor antagonist) on evoked 3H overflow, but considerably decreased the inhibitory effect of clonidine or B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[5,4-d]-azepine). The present results suggest that the serotoninergic nerve terminals in the rat brain cortex are endowed with an adenylate cyclase, which is negatively coupled to the presynaptic alpha 2-adrenoceptors, but is not linked to the presynaptic autoreceptors.
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PMID:Facilitation of serotonin (5-HT) release in the rat brain cortex by cAMP and probable inhibition of adenylate cyclase in 5-HT nerve terminals by presynaptic alpha 2-adrenoceptors. 282 46

Although vasoactive intestinal peptide (VIP)-immunoreactive nerves have been identified around the eccrine sweat glands, their functional significance is unknown. We found that VIP evokes eccrine sweat secretion in isolated monkey palm eccrine sweat glands in vitro as profusely as does isoproterenol (Iso), however, at concentrations two orders of magnitude lower than that of Iso. Like Iso sweating, the VIP sweating was relatively insensitive to removal of Ca2+ from the medium. The time course of adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in the secretory coil paralleled that of sweat secretion. However, unlike Iso stimulations, both VIP-induced cAMP level and VIP sweat rate markedly declined with time. The attenuation of VIP sweat rate was reversed by forskolin and by theophylline, suggesting that the attenuation is caused partially by desensitization of the receptor-cyclase complex and/or by cAMP breakdown by phosphodiesterase. Forskolin stimulated the VIP-induced cAMP level more than can be expected from a simple additive effect. The sudorific effects of a submaximal concentration of VIP (6 X 10(-9) M) and that of methacholine (MCh) (10(-8) M) were only additive. The VIP-induced cAMP level was markedly augmented by MCh and further enhanced by Iso with or without theophylline. Thus the most salient biochemical consequence of the VIP-ergic component of sweat gland innervation is to induce synergistic amplification of tissue cAMP accumulation. The functional significance of synergistically accumulated cAMP in physiological eccrine sweating remains to be studied.
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PMID:Effect of VIP on sweat secretion and cAMP accumulation in isolated simian eccrine glands. 282 8

1. Using the rat superior cervical ganglion in vitro, the relative efficacy of nicotinic synaptic transmission was estimated by recording the postganglionic compound action potential and the amount of endogenous acetylcholine (ACh) released. These two parameters were correlated in individual ganglia by sampling the bathing medium for the assay of ACh while simultaneously recording the postganglionic response. 2. The beta-adrenoceptor agonist isoprenaline potentiated both the evoked release of ACh and the postganglionic response by about 20% during preganglionic stimulation at 0.2 Hz. 3. The adenosine receptor agonist 2-chloroadenosine inhibited ACh release and the postganglionic response by about 35%. 4. Tetanic preganglionic stimulation for a few seconds induced a long-term potentiation of nicotinic responses and of ACh release. Both of these potentiations were dependent upon extracellular Ca2+ during the tetani. 5. Forskolin and analogues of cyclic AMP also caused a long-lasting potentiation of both the evoked release of ACh and the postganglionic response, indicating that cyclic AMP may regulate transmission by a presynaptic mechanism. The specificity of the cyclic AMP analogues was tested using various butyryl- and bromo-purine nucleotides. 6. The effects of forskolin and 8-bromo-cyclic AMP did not appear to be dependent upon extracellular Ca2+. 7. The potentiation caused by forskolin was consistently augmented by three phosphodiesterase inhibitors--AH 21-132, papaverine and SQ 20-006. However, the effect of forskolin was not consistently enhanced by theophylline, nor was it reduced by the adenylate cyclase inhibitor SQ 22-536. 8. The neurogenic long-term potentiation was augmented by two of the phosphodiesterase inhibitors that also augmented the forskolin-induced potentiation--papaverine and SQ 20-006. 9. It was concluded that cyclic AMP can enhance nicotinic transmission, and can do so by increasing the evoked release of ACh. However, it was not possible to prove that cyclic AMP mediates the long-term potentiation induced by tetanic preganglionic stimulation.
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PMID:Long-term regulation of synaptic acetylcholine release and nicotinic transmission: the role of cyclic AMP. 283 71

The effects of forskolin, 3,5,3'-L-triiodothyronine, and isobutyl methylxanthine on the accumulation of cyclic AMP were studied in rat thymocytes in vitro. Forskolin was found to stimulate markedly the production of intracellular cAMP which was partially released from the cells into the medium. Isobutyl methylxanthine, an inhibitor of cAMP phosphodiesterase, markedly potentiated the effect of forskolin on intracellular cAMP concentration, while triiodothyronine was ineffective. However, triiodothyronine acted synergically with forskolin and/or isobutyl methylxanthine. It was confirmed that low forskolin concentrations modulate the effects of the hormone.
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PMID:Effects of forskolin and triiodothyronine on cyclic AMP production in rat thymocytes. 283 60

Forskolin, a direct activator of adenylate cyclase, modifies the voltage-dependent K+ conductance of quiescent human peripheral blood T lymphocytes. In the presence of greater than 20 microM forskolin, the average voltage-gated current in whole-cell patch clamp is significantly decreased. The voltage dependence and kinetics of activation are not changed from untreated control cells. However, inactivation becomes biphasic. Much of the current inactivates very quickly (complete in 10 ms), and the remaining outward current inactivates more slowly with a time constant closer to that of control cells. To determine whether this effect is mediated by a rise in intracellular cAMP, cells were preincubated and subsequently voltage-clamped in the presence of other agents that raise the cAMP levels in T cells (isoproterenol plus a phosphodiesterase inhibitor, or dibutyryl cAMP) with no effect on the K+ conductance. Similarly, cells put in whole-cell patch clamp with cAMP, GTP, ATP, and theophylline added to the electrode filling solution showed no change in K+ current. Because other procedures that raise cAMP did not duplicate the effect of forskolin, we investigated the effect of 1,9-dideoxyforskolin, an analogue of forskolin that does not stimulate adenylate cyclase in human lymphocytes. This drug induced changes in the whole-cell K+ conductance identical to those observed with forskolin. Both forskolin and dideoxyforskolin inhibit mitogen-induced proliferation of lymphocytes. Because inhibition of proliferation occurs in the presence of known K+ channel blockers, these results suggest that forskolin has an effect on T cell mitogenesis that is mediated by inhibition of K+ conductance and is independent of cAMP.
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PMID:Forskolin effects on the voltage-gated K+ conductance of human T cells. 284 53

We have investigated the type of purine receptor in the guinea-pig olfactory cortex, using pial surfaces slices maintained in vitro. Adenosine (0.1 to 100 mumol/l) bath applied in the presence of the uptake inhibitor nitrobenzylthioinosine, depressed the evoked potentials in a dose related fashion. Synthetic and uptake resistant adenosine analogues had the same effect as adenosine and the order of potency of these was: 5'-N-ethylcarboxamide adenosine greater than L-N6-phenylisopropyl adenosine (L-PIA) = N6-cyclohexyladenosine = 2-chloroadenosine greater than adenosine greater than D-N6-phenylisopropyladenosine (D-PIA). The D-stereoisomer of PIA was 45 times less potent than L-PIA. The methylxanthine compounds 8-phenyltheophylline (3 mumol/l) and 3-isobutyl-1-methylxanthine (50 mumol/l) antagonised the depression produced by L-PIA. Rolipram, a phosphodiesterase inhibitor, in concentrations up to 100 mumol/l had no effect on the evoked potentials or on adenosine action. Forskolin, a cAMP stimulant, slightly increased the amplitude of the evoked potential, and partly reversed the depressant effect of adenosine. Noradrenaline had no effect either alone or in the presence of adenosine. The results of these experiments indicate the existence of A1 subtype adenosine receptors in the guinea pig olfactory cortex probably linked to a depression of intracellular cAMP.
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PMID:Adenosine-induced depression of synaptic transmission in the isolated olfactory cortex: receptor identification. 298 40

Alterations in the cyclic AMP-dependent protein kinase activity ratio in response to putative neurotransmitters and other cyclic AMP-elevating agents in intact cerebral cortical slices and Krebs-Ringer particulate preparations from cerebral cortex were examined. Both norepinephrine (30 microM) and forskolin (20 microM) produced a time-dependent increase in intracellular levels of cyclic AMP in cerebral cortical slices which was paralleled by an increase in both cyclic AMP and the protein kinase activity ratio. The increases were maximal at 5 min. and remained elevated for at least 15 min. Forskolin, norepinephrine, adenosine and isoproterenol produced a concentration-dependent increase in both cyclic AMP and the protein kinase activity ratio, however, the degree of increase observed was dissimilar. Thus, a 5-fold change in intracellular cyclic AMP resulted in only a 2-fold increase in the activity ratio. Of the agents examined, forskolin produced the most marked change in the activity ratio (from 0.23 to 0.78 at 100 microM) while isoproterenol at 100 microM produced only a 50% increase in the activity ratio. The half-time for the decline in forskolin elicited elevations of either the activity ratio or cyclic AMP was about 4-6 min. In the presence of the phosphodiesterase inhibitor, Ro 20-1724, both were significantly prolonged being 60-70% of the maximum observed immediately after forskolin stimulation, at 15 min. Potentiation of forskolin elicited increases in the activity ratio by Ro 20-1724 were also observed but the increase in the activity ratio was maximal at 7.5 min. while cyclic AMP accumulations continued to rise during the entire 15 min. incubation. Particulate preparations from cerebral cortex were found to contain a cyclic AMP-dependent protein kinase which could be activated 2 to 3-fold with either forskolin, norepinephrine, or adenosine. Unlike the intact brain slice the changes in protein kinase activity ratio and intracellular levels of cyclic AMP in cell-free particulate preparations were similar in both time and degree.
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PMID:Regulation of adenosine 3':5'-monophosphate-dependent protein kinase in cerebral cortex. 298 40


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