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 effects of serotonin receptor agonists and antagonists on the electrically (3 Hz) evoked 3H overflow were determined on pig brain cortex slices preincubated with 3H-serotonin and superfused with physiological salt solution containing indalpine (an inhibitor of serotonin uptake) plus phentolamine. The potencies of the serotonin receptor agonists and antagonists were compared with their affinities for 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D binding sites in pig or rat tissue membranes; in addition, the potencies of the agonists were compared to their potencies in inhibiting adenylate cyclase activity in membranes of calf substantia nigra. In the superfusion experiments on pig brain cortex slices the following rank orders of potencies were obtained: agonists, serotonin greater than 5-methoxytryptamine = 5-carboxamidotryptamine greater than RU 24969 (5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole) greater than SDZ 21009 (4(3-terbutylamino-2-hydroxypropoxy)indol-2-carbonic-acid-isopr opylester) greater than or equal to yohimbine greater than or equal to cyanopindolol greater than 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) greater than or equal to CGS 12066 B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline); ipsapirone and urapidil were ineffective; antagonists (antagonism determined against 5-methoxytryptamine as an agonist), metitepine greater than metergoline greater than mianserin. Propranolol, spiperone or mesulergine did not produce a shift of the concentration-response curve for 5-methoxytryptamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The pharmacological properties of the presynaptic serotonin autoreceptor in the pig brain cortex conform to the 5-HT1D receptor subtype. 279 14

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

The trematode Schistosoma mansoni possesses an adenylate cyclase that is stimulated by serotonin. During development from the newly transformed schistosomulum to the adult stage, the serotonin-stimulated activity of adenylate cyclase increases. Our results show that the apparent affinity of the receptor for serotonin is the same at all stages tested. Serotonin receptors were characterized by testing the ability of agonists and antagonists to influence cyclase activity. The order of potency of antagonists is similar to that seen in Fasciola hepatica and is different from that characteristic of mammalian serotonin receptors. The nature of serotonin receptors in S. mansoni appears to be unchanged during development from cercaria to adult. Forskolin, which activates adenylate cyclase at the catalytic subunit, increases cyclase activity at all stages of development with no change in affinity. Forskolin and serotonin act synergistically to activate cyclase, and the degree of potentiation is the same (four-fold) at all stages of development, indicating that the coupling between the serotonin receptor and the catalytic component of cyclase is fully developed in the schistosomulum. The synergism between serotonin and forskolin is characterized by an increase in Vmax with no effect on the affinity for either serotonin or forskolin. The Ka for potentiation of serotonin action by forskolin is lower than the Ka for direct activation of cyclase by forskolin. The change in adenylate cyclase activity during development from schistosomulum to adult does not appear to be attributable to a change in the nature of the serotonin receptor, the catalytic component, or the coupling mechanism between these two components. Instead, there appears to be an increase in the total receptor-coupled enzyme system.
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PMID:Nature of serotonin-activated adenylate cyclase during development of Schistosoma mansoni. 343 67

An adenylate cyclase (EC 4.6.1.1) that is activated specifically by low concentrations of serotonin has been identified in homogenates of the thoracic ganglia of an insect nervous system. The activation of this enzyme by serotonin was selectively inhibited by extremely low concentrations of D-lysergic acid diethylamide (LSD), 2-bromo-LSD, and cyproheptadine, agents which are known to block certain serotonin receptors in vivo. The inhibition was competitive with respect to serotonin, and the calculated inhibitory constant of LSD for this serotonin-sensitive adenylate cyclase was 5 nM. The data are consistent with a model in which the serotonin receptor of neural tissue is intimately associated with a serotonin-sensitive adenylate cyclase which mediates serotonergic neurotransmission. The results are also compatible with the possibility that some of the physiological effects of LSD may be mediated through interaction with serotonin-sensitive adenylate cyclase.
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PMID:Serotonin-sensitive adenylate cyclase in neural tissue and its similarity to the serotonin receptor: a possible site of action of lysergic acid diethylamide. 459 72

Dopaminergic agonists which act on adenylate cyclase-linked dopamine receptor sites (D1-type) (dopamine, apomorphine and ADTN) induced a dose-dependent increase in the incorporation of L-fucose and D-mannose into glycoproteins of hippocampal, striatal and cortical slices of rat and mouse brain, whilst in rat liver slices dopamine failed to elicit such alterations in protein glycosylation. Testing in slices of rat hippocampus dopaminergic agonists with selective affinity to D2-receptors (bromocriptine, ergometrine) no changes in sugar incorporation into glycoproteins of rat hippocampus were observed. Dopamine stimulated L-fucose incorporation into rat hippocampal glycoproteins was inhibited to a different degree, but almost incompletely by dopamine receptor antagonists like haloperidol, D-butaclamol, promazine and alpha-flupenthixol, whilst chloropromazine and the selective D2-receptor antagonist sulpiride were without any effects. Also serotonin receptor antagonists (cinanserine) and beta-adrenergic receptor blockers (pindolol, alprenolol, practolol) failed to interfere with this dopamine action. But D,L-propranolol enhanced dopamine stimulated glycosylation of rat hippocampal proteins in an additive synergistic manner. This effect appeared to be not related to the antagonistic action of propranolol on beta-adrenergic receptor sites. From our results it is concluded that interactions with dopamine receptor sites (D1-type) is only one part of the mechanism triggering dopamine stimulated glycosylation of brain proteins in vitro.
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PMID:Dopamine stimulated glycosylation of brain proteins in vitro is inhibited only partially by dopamine receptor antagonists. 614 36

Addition of serotonin to the medium bathing an Aplysia abdominal ganglion causes a change in the endogenous bursting activity of the identified neuron R15. At serotonin concentrations in the micromolar range, the predominant effect is an increase in depth and duration of the interburst hyperpolarization and consequent decrease in burst rate. At higher concentrations (10 microM) serototin can inhibit bursting completely. We have shown previously that these changes can be mimicked by bath application or intracellular injection of several cyclic AMP analogs substituted at the 8 position. Voltage clamp analysis indicates that serotonin and cyclic AMP analogs both cause an increase in membrane slope conductance in R15, with reversal potentials for the responses between -75 and -80 mV, close to the K+ equilibrium potential. When the K+ concentration in the bathing medium is changed, the reversal potentials change in a manner suggesting that serotonin and cyclic AMP analogs on K+ conductance are not additive. Furthermore, the effects of low concentrations of serotonin can be potentiated by the phosphodiesterase inhibitor Ro 20-1724. A pharmacological analysis indicates that the serotonin receptor that mediates hyperpolarization in R15 is similar to the serotonin receptor that we have shown to be coupled to adenylate cyclase. The present electrophysiological and pharmacological observations, together with our previous biochemical and pharmacological results, demonstrate that the serotonin-induced hyperpolarization of neuron R15 is mediated by cyclic AMP.
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PMID:Serotonin-induced hyperpolarization of an indentified Aplysia neuron is mediated by cyclic AMP. 625 53

Computer-assisted quantitative analysis of radioligand binding to rat cortical S2 serotonin receptors indicates the existence of two affinity states of the same receptor population. Monophasic antagonist competition curves for [3H]ketanserin-labelled sites suggest a uniform population of receptors with one affinity state for antagonists. Biphasic competition curves of agonists suggest that agonists discriminate high- and low-agonist-affinity forms of the S2 receptors. The affinities of agonists for the high- and low-affinity states, and the apparent percentages of high agonist-affinity forms varies with different agonists. The guanine nucleotides GTP and guanyl-5'-imido-diphosphate [Gpp(NH)p], as well as divalent cations, modulate the proportion of the sites with high affinity for agonists as evidenced by their ability to shift the agonist competition curves for [3H]ketanserin-labelled S2 receptors. GTP and Gpp(NH)p effects appear to be agonist-specific, as they do not affect antagonist competition for [3H]ketanserin-labelled S2 receptors, or [3H]ketanserin binding to S2 receptors. ATP and ADP have little or no effect on the binding properties of S2 serotonin receptors, whereas GDP is less potent than GTP. The presence of these specific nucleotide effects are the first evidence suggesting involvement of a guanine nucleotide-binding protein in the mechanism of agonist interaction with the S2 serotonin receptor. In general, the binding properties of [3H]ketanserin-labelled S2 serotonin receptors strongly resemble those of adenylate-cyclase coupled receptors such as the beta-adrenergic, the alpha 2-receptor, and the D-2 dopamine receptor. This may indicate the S2 serotonin receptor is coupled to adenylate cyclase activity, through a GTP binding protein.
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PMID:Guanyl nucleotide and divalent cation regulation of cortical S2 serotonin receptors. 649 56

Many radiolabelled receptors coupled to intracellular adenylate cyclase activity have been found to be modulated by physiological modulators such as GTP (guanosine triphosphate) and Gpp(NH)p (guanosine-imido-diphosphate). In particular, the apparent affinity of agonists competing for the binding of 3H-antagonist-labelled receptors is reduced in the presence of GTP and Gpp(NH)p. We report herein the agonist-specific effects of GTP and Gpp(NH)p on rat brain cortical S2 serotonin receptors. The agonists serotonin, 5-methoxytryptamine, bufotenine, and tryptamine display threefold lower affinities for S2 serotonin receptors in the presence of 10(-4)M GTP or Gpp(NH)p than in the absence of the nucleotides. The antagonists spiperone, cinanserin, cyproheptadine and methysergide are unaffected by the guanine nucleotides. The Hill coefficients of the agonists increase from between 0.70-0.80 to 0.90-1.00 due to guanine nucleotides. ATP, ADP, and GDP have little or no effect. This pattern of guanine nucleotide effects has been found with receptors which are modulated by a guanine nucleotide regulatory protein and may indicate that the S2 serotonin receptor may be coupled to intracellular adenylate cyclase activity.
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PMID:Guanine nucleotides modulate cortical S2 serotonin receptors. 652 58

Muscle fibres isolated from adult Schistosoma mansoni contracted in a dose-dependent manner when exposed to elevated K+ with a maximum response obtained with 25 mM K+. These contractions were dependent on extracellular Ca2+ since Co2+ (5 mM) or nicardipine (1 microM) blocked the high K+ contractions. Serotonin (300 nM or higher) was required for maintenance of high K+ contractions. With concentrations of serotonin less than 300 nM the response was dose dependent. 5-Methoxytryptamine or alpha-methylserotonin at 1 microM as well as 10 microM tryptamine were able to substitute for serotonin, but 1 microM 5-carboxyamidotryptamine was ineffective. The order of potency for antagonists (10 microM) was: methiothepin > metergoline > Ly-278,584 = ketanserin. This pattern of responsiveness does not fit well with any known mammalian serotonin receptor subtype. Since forskolin, an adenylate cyclase activator, is able to mimic the action of serotonin and H89, a protein kinase inhibitor, is able to block the effect of serotonin, the effect of serotonin on contractility of the muscle may be via a cAMP-dependent pathway.
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PMID:Serotonin and its requirement for maintenance of contractility in muscle fibres isolated from Schistosoma mansoni. 800 57

Biochemical and electrophysiological approaches were used to assess the possible changes in 5-hydroxytryptamine (serotonin) 5-HT1A receptors in the rat brain after a long-term treatment with cericlamine [2-(3,4-dichlorobenzyl)-2-dimethylamino-1-propanol], a novel serotonin reuptake inhibitor with antidepressant properties. Possible changes in other serotonin receptor binding sites (5-HT2A, 5-HT2C and 5-HT3) were also investigated after this treatment. Cericlamine was injected for 2 weeks at a dose (16 mg/kg i.p., twice daily) that ensured complete prevention of 4-methyl-alpha-ethyl-meta-tyramine-induced depletion of brain serotonin. In vitro binding and quantitative autoradiographic studies showed that neither 5-HT1A, 5-HT2A, 5-HT2C nor 5-HT3 receptor binding sites in various brain areas were affected by the 14-day treatment with cericlamine. Although forskolin-stimulated adenylate cyclase activity was significantly increased in hippocampal homogenates from cericlamine-treated rats, the reduction in this enzymatic activity due to 5-HT1A receptor stimulation by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unchanged in these animals as compared with controls. In contrast, in vitro and in vivo electrophysiological recordings of serotoninergic neurons in the dorsal raphe nucleus revealed a clearcut functional desensitization of somatodendritic 5-HT1A autoreceptors. Thus the potency of 8-OH-DPAT and ipsapirone to depress the firing rate of these neurons in brain stem slices was significantly reduced after the 2-week treatment with cericlamine. In vivo, the potency of an injection of cericlamine to inhibit the discharge of serotoninergic neurons was also markedly less in rats that had been pretreated for 2 weeks with this drug as compared with controls. However, the inhibitory effects of systemically injected 8-OH-DPAT and ipsapirone on the electrical activity of serotoninergic neurons were as pronounced in cericlamine-treated rats as in controls. In addition, the reduction in serotonin synthesis due to an acute treatment with 8-OH-DPAT (0.1 or 0.3 mg/kg s.c.) was not significantly different in both groups of rats. These data support the idea that postsynaptic (in the hippocampus) and somatodendritic (in the dorsal raphe nucleus) 5-HT1A receptors are differently regulated in the rat brain, because only the latter receptors desensitized after a long-term blockade of serotonin reuptake by cericlamine. They also suggest that the inhibitory influence of systemically administered direct 5-HT1A agonists such as 8-OH-DPAT and ipsapirone on the electrical and metabolic activity of serotoninergic neurons does not result solely from the stimulation of somatodendritic 5-HT1A autoreceptors.
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PMID:Central pre- and postsynaptic 5-HT1A receptors in rats treated chronically with a novel antidepressant, cericlamine. 813 56


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