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)

In superfused rat hypothalamic slices prelabeled with [3H]-5-hydroxytryptamine [( 3H]-5-HT), the 5-HT autoreceptor agonists 5-methoxytryptamine and RU 24969 inhibited in a concentration-dependent manner the electrically evoked release of [3H]-5-HT. Exposure to phorbol-12,13-dibutyrate increased in a concentration-dependent manner the stimulation-evoked overflow of [3H]-5-HT and shifted to the right the 5-methoxytryptamine inhibition curve. Exposure to forskolin, a potent activator of adenylate cyclase, increased the stimulation-evoked [3H]-5-HT overflow and shifted to the left the 5-methoxytryptamine or RU 24969 inhibitory curves on transmitter release. A similar interaction was observed in the presence of 1-isobutyl,3-methylxanthine (IBMX), a phosphodiesterase inhibitor, or 8-bromo-cyclic AMP and the serotonin autoreceptor agonist 5-methoxytryptamine. In the presence of phorbol-12,13-dibutyrate or forskolin, the enhancing effect of the 5-HT autoreceptor antagonist methiothepin on the stimulation-evoked [3H]-5-HT overflow was significantly less pronounced than in the absence of these compounds. These results indicate that the presynaptic 5-HT autoreceptors that modulate the release of [3H]-5-HT in rat hypothalamic slices may be coupled to the phosphoinositide cycle and protein kinase C-dependent mechanisms. In addition, the increase in intracellular level of cyclic AMP by forskolin, IBMX, and 8-bromo-cyclic AMP potentiates the inhibitory effects of the autoreceptor agonist 5-methoxytryptamine on [3H]-5-HT release, although the mechanism of the interaction remains to be elucidated.
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PMID:Phorbol-12,13-dibutyrate antagonizes while forskolin potentiates the presynaptic autoreceptor-mediated inhibition of [3H]-5-hydroxytryptamine release in rat hypothalamic slices. 247 Jan 60

Serotonin has no obvious effect on basal cyclic AMP levels but reduces the forskolin-, isoproterenol-, and vasoactive intestinal peptide-induced stimulation of cyclic AMP levels in a dose-dependent manner. Serotonergic, cholinergic, muscarinic, alpha-adrenergic, and dopaminergic antagonists have no effect on the serotonin response. Topical application of a serotonin/pargyline solution to the living eye causes desensitisation of the serotonin response in the iris-ciliary body, an observation confirming the presence of specific serotonergic receptors linked to adenylate cyclase. The 5-HT1A [5-hydroxytryptamine (serotonin) type 1A] receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin and buspirone mimic the serotonin response in reducing the forskolin-stimulated cyclic AMP levels, as do the indole derivatives 5-methoxytryptamine, 5-hydroxtryptophan, and tryptamine. However, the ineffectiveness of the 5-HT1A agonist ipsapirone and the inability of spiroxatrine to block the serotonin response show that classical 5-HT1A receptors are not involved. The serotonin response is blocked by pertussis toxin and is insensitive to the phosphodiesterase inhibitor theophylline, which indicates the involvement of an inhibitory guanine regulatory protein in the coupling of the serotonin receptor to the adenylate cyclase catalytic unit.
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PMID:Evidence for the presence of serotonin receptors negatively coupled to adenylate cyclase in the rabbit iris-ciliary body. 254 97

Melatonin signal transduction was examined in median eminence/pars tuberalis (ME/PT) explants from Djungarian hamsters. High affinity melatonin receptors in hamster ME/PT were first quantified by in vitro autoradiography using the potent melatonin agonist 125I-labeled melatonin ([125I]MEL). Scatchard analysis of [125I]MEL binding in ME/PT revealed high affinity receptors [dissociation constant (Kd) = 2.75 X 10(-11) M]. [125I]MEL binding was markedly reduced by guanine nucleotides; treatment with the nonhydrolyzable GTP analog guanosine 5'-O-(3-thiotriphosphate) caused a 10-fold decrease in receptor affinity. Melatonin (10 nM) significantly inhibited forskolin-stimulated cAMP accumulation in ME/PT, but not in pituitary or pineal glands. In ME/PT explants, melatonin and 6-chloromelatonin inhibited forskolin-stimulated cAMP accumulation in a dose-dependent manner with similar potency (significant inhibition for each at concentrations greater than or equal to 100 pM). Serotonin significantly inhibited forskolin-stimulated cAMP levels only at doses greater than or equal to 100 microM. Inhibition of [125I]MEL binding in ME/PT by these three indolamines paralleled that determined for inhibition of forskolin-stimulated cAMP accumulation. Pertussis toxin treatment (1 microgram/ml) blocked the ability of melatonin (10 nM) to inhibit forskolin-stimulated cAMP accumulation and significantly reduced [125I]MEL binding. Pertussis toxin ADP-ribosylated the alpha-subunits of at least two guanine nucleotide-binding proteins in ME/PT explants with molecular weights of approximately 40 K. Melatonin did not increase phosphodiesterase activity in ME/PT explants. The results strongly suggest that a signal transduction pathway for melatonin in mammals involves inhibition of adenylyl cyclase by a pertussis toxin-sensitive guanine nucleotide-binding protein.
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PMID:Melatonin signal transduction in hamster brain: inhibition of adenylyl cyclase by a pertussis toxin-sensitive G protein. 255 62

1. The monoamines serotonin (5-HT) and octopamine (OA) enhance the expression of swimming activity in the medicinal leech (Willard, 1981; Belanger and Orchard, 1988). We explored further the effects of these monoamines and related agents on swimming activity observed in isolated leech nerve cords. 2. We confirmed that swimming activity is induced reversibly following exposure of the nerve cord to 5-HT (50 microM); the half-maximal rate of swimming activity develops in about 15 min. Swimming activity returns to control levels about 30 min after drug washout. 3. Swim-induction by 5-HT is blocked by the presence of 10 microM cyproheptadine (a 5-HT antagonist). 4. Although apparently less effective than 5-HT, OA application to nerve cords also induced swimming activity. 5. Depletion of endogenous amines from nerve cords by acute exposure to reserpine (10-150 microM) blocked stimulus-evoked swimming activity within 4 hr. 6. Subsequent application of 5-HT (50 microM) or OA (100 microM) reinstated stimulus-evoked swimming and induced repeated episodes of non-triggered swimming activity. 7. Application of cAMP and cAMP analogs, as well as phosphodiesterase inhibitors (theophylline and IBMX), mimicked the effects of the monoamines, suggesting that 5-HT and OA may activate swimming activity by increasing neuronal cAMP. 8. We obtained episodes of swim-like activity from individual, isolated ganglia exposed to 5-HT or OA. Such episodes were usually brief, with variable cycle period. 9. We conclude that individual nerve cord ganglia contain the complete neuronal circuitry required to generate the rudiments of swimming activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of swimming activity in the medicinal leech by serotonin and octopamine. 257 40

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

In the preceding paper (Kramer and Levitan, 1988), we presented evidence that an inwardly rectifying K+ current (IR) is inactivated by Ca2+ influx accompanying spontaneous bursting activity in the Aplysia neuron R15. In this paper we examine the mechanism that enables Ca2+ to inactivate IR. Since IR is enhanced by cyclic AMP in neuron R15 (Drummond et al., 1980; Benson and Levitan, 1983), we examined the Ca2+-dependent inactivation of IR after application of either serotonin (5-HT), the adenylate cyclase activator forskolin, or a membrane-permeable cAMP analog, all agents that increase cAMP and hence the magnitude of IR. Even though more active IR channels are available under these conditions, less Ca2+-dependent inactivation is observed. This is contrasted with the Ca2+-dependent inactivation of the voltage-gated Ca2+ current (ICa). Elevating cAMP enhances ICa in R15 and also increases its Ca2+-dependent inactivation. Hence the mechanisms whereby Ca2+ inactivates IR and ICa appear to differ from each other. Elevating internal Ca2+ by repeatedly depolarizing the neuron suppresses the response of IR to brief applications of 5-HT, and speeds the relaxation of the response, suggesting that Ca2+ can interfere with the cAMP-dependent activation of IR. One biochemical site where Ca2+ can reduce cellular cAMP is by activating the Ca2+/calmodulin-sensitive form of phosphodiesterase. We have detected such enzyme activity in homogenates of Aplysia abdominal ganglia and extracts of single R15 somata. Inhibitors of the phosphodiesterase activity suppress the Ca2+-dependent inactivation of IR. Finally, we have used a radioimmunoassay to measure cAMP in individual R15 somata, and have found that R15 neurons hyperpolarized for prolonged periods contain more cAMP than do R15 neurons allowed to burst, consistent with the hypothesis that Ca2+ influx reduces cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of calcium-dependent inactivation of a potassium current in Aplysia neuron R15: interaction between calcium and cyclic AMP. 283 52

Micropressure ejection of serotonin (5-hydroxytryptamine, 5-HT) produced excitatory responses in the L14 ink motor neurons of Aplysia that depended on the site of application. Ejection of 5-HT onto the cell body produced a slow response that showed variability in voltage sensitivity between preparations. In contrast, ejection of 5-HT onto the neuropil underneath the cell body produced a response whose amplitude was consistently a linear function of the holding potential, reversing near the predicted potassium equilibrium potential. Subsequent analyses focused on this second response. The neuropil response induced by 5-HT had a linear current-voltage relationship (reversing at ca. -80 mV), was associated with a decrease in input conductance, and was sensitive to changes in the concentration of extracellular K+. Serotonin application in artificial seawater (ASW) containing 30 mM K+ produced a response that reversed close to the altered Nernst potential for K+. The 5-HT response did not appear to be due to secondary activation of interneurons or to depend primarily on extracellular Ca2+, since ejection of 5-HT onto cells bathed in ASW containing 30 mM Co2+ produced responses comparable to, although somewhat attenuated from, those observed in ASW. Serotonin responses similar to those produced in ASW were obtained after perfusing the ganglion with ASW containing Co2+, 4-aminopyridine (4-AP), and tetraethylammonium (TEA). This suggests that the 5-HT-sensitive current is separate from the Ca2+-activated, fast, and delayed rectifying K+ currents. The 5-HT response appeared to be mediated by changes in levels of cAMP. Bath application of the phosphodiesterase inhibitors IBMX (3-isobutyl-1-methylxanthine) or Ro 20-1724, or the adenylate cyclase activator forskolin mimicked the 5-HT response by producing a slow inward current associated with a decrease in membrane conductance. Alteration of cellular cAMP metabolism modulated the response to 5-HT. Exposure of the ganglion to low concentrations of either Ro 20-1724 or forskolin potentiated the 5-HT response. Higher concentrations of these agents largely blocked the response to subsequent 5-HT applications. Bath application of the 8-bromo derivative of either cAMP or cGMP produced a slow inward current associated with a decrease in membrane conductance in cells voltage clamped at the resting potential. Responses to 5-HT were blocked, however, after exposure to 8-bromo-cAMP, but not to 8-bromo-cGMP. These results suggest that 5-HT produces a voltage-independent decrease in a steady-state potassium conductance that may be mediated by cAMP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Analysis of decreased conductance serotonergic response in Aplysia ink motor neurons. 298 53

Imidazole, a phosphodiesterase stimulator potentiated the responses of rat uterus to 5-HT, without increasing the maximal response. Aminophylline, papaverine and diazoxide significantly inhibited the responses to 5-HT including the maximal response. Imidazole did not affect the inhibitory effect of aminophylline, papaverine and diazoxide. The effect of imidazole on myometrium may be due to its direct effect on membrane permeability resulting in an increased influx of calcium. Phosphodiesterase stimulation if at all seems to play only a minor role.
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PMID:Modulation of 5-hydroxytryptamine-evoked responses of the isolated rat uterus by imidazole, a phosphodiesterase stimulator. 299 37

Protein phosphorylation catalysed by cyclic AMP-dependent, Ca2+/calmodulin-dependent and Ca2+/diacylglycerol-dependent protein kinases is important both in the modulation of synaptic transmission and in the regulation of neuronal membrane permeability (for reviews see refs 5-7). However, there has previously been no evidence for the involvement of cyclic GMP-dependent protein kinase (cGMP-PK) in the regulation of neuronal function. Serotonin induces an increase of Ca2+ current in a group of identified ventral neurones of the snail Helix aspersa. This effect is probably mediated by cGMP because it is mimicked by the intracellular injection of cGMP or the application of zaprinast, an inhibitor of cGMP-dependent phosphodiesterase. We have now found that the effect of either serotonin or zaprinast on the Ca2+ current is potentiated by the intracellular injection of cGMP-PK. Moreover, the intracellular injection of activated cGMP-PK (cGMP-PK + 1 microM cGMP) greatly enhances the Ca2+ current of the identified ventral neurones seen in the absence of serotonin. These results indicate that cGMP-PK has a physiological role in the control of the membrane permeability of these neurones.
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PMID:cGMP-dependent protein kinase enhances Ca2+ current and potentiates the serotonin-induced Ca2+ current increase in snail neurones. 302 54

Plasma membranes were isolated from pig platelets after glycerol facilitated lysis by sucrose density gradient centrifugation. The purity of the membrane fraction was followed by electron microscopy, gel electrophoresis and analysis of acid phosphatase (EC 3.1.3.2) and phosphodiesterases (EC 3.1.4.1). (3H)5-Hydroxytryptamine ([3H]5-HT) was bound to two saturable binding sites of the membranes. The KD value for the high affinity sites was 0.85 nM and for the low affinity sites 0.48 microM. With the exception of tryptamines little or no (3H)5-HT was displaced by serotonin antagonists and uptake inhibitors suggesting another type of binding than that of 5-HT1. Apparently, enhancement of binding in the presence of Na+ was due to stimulation of an uptake process. Binding of (3H)ketanserin and (3H)LSD to pig platelet membranes showed the characteristics of 5-HT2 binding sites previously identified in rat brain. Since ketanserin inhibited 5-HT induced aggregation of pig platelets (IC50 = 14.2 nM), the ketanserin binding sites can be classified as 5-HT2 receptors. The functional properties of these binding sites and their density in pig platelets as compared with brain membranes may motivate studies on 5-HT2 receptors in pig platelets as models for those in nerve endings.
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PMID:Characterization of 5-hydroxytryptamine binding sites in the plasma membrane of pig blood platelets. 315 78


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