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)

This study examined the effects of dopamine D1 and D2 receptor agonists and antagonists on the spontaneous and calcium-dependent, K+-induced release of gamma-[3H]aminobutyric acid [( 3H]GABA) accumulated by slices of rat substantia nigra. SKF 38393 (D1 agonist) and dopamine (dual D1/D2 agonist) were without effect on [3H]GABA efflux by themselves (1-40 microM), or in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) (0.5 mM), but potentiated evoked release in the presence of forskolin (0.5 microM), an adenylate cyclase activator. These increases in release were prevented by the D1 antagonist SCH 23390 (0.5 microM), but not by the D2 antagonist metoclopramide (0.5 microM). Higher concentrations of forskolin (10-40 microM) augmented stimulus-evoked [3H]GABA release directly, whereas dibutyryl cyclic AMP (100-200 microM) depressed it. Apomorphine, noradrenaline, and 5-hydroxytryptamine (1-40 microM) had no effect. The D2 stimulants lisuride, RU 24213, LY 171555, and bromocriptine dose-dependently inhibited depolarisation-induced but not basal [3H]GABA outflow. These inhibitory responses were not modified by the additional presence of SKF 38393 (10 microM) or SCH 23390 (1 microM), or by injection of 6-hydroxydopamine into the medial forebrain bundle 42 days earlier, but were attenuated by metoclopramide (0.5 microM). Higher amounts (10 microM) of SCH 23390, metoclopramide, or other D2 antagonists (loxapine, haloperidol) reduced evoked GABA release by themselves, probably by nonspecific mechanisms. These results suggest D1 and D2 receptors may have opposing effects on nigral GABA output and could explain the variable effects of mixed D1/D2 dopaminomimetics in earlier release and electrophysiological experiments.
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PMID:Opposing roles of dopamine D1 and D2 receptors in nigral gamma-[3H]aminobutyric acid release? 295 68

We measured the inhibition of forskolin-stimulated adenylate cyclase by 5-hydroxytryptamine (5-HT) and other serotonin agonists in rat substantia nigra homogenates. 5-HT, 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)indole (RU 24969), 5-carboxamidotryptamine (5-CT), 1-(m-trifluoromethyl-phenyl)piperazine (TFMPP) and tryptamine inhibited forskolin-stimulated adenylate cyclase with EC50 of 67, 40, 83, 100 and 200 nM respectively. 8-Hydroxydipropylaminotetralin (8-OH-DPAT) and ipsapirone, both 5-HT1A-selective drugs, were respectively weak and ineffective to inhibit forskolin-stimulated adenylate cyclase. CGS 120 66B was almost as potent (EC50 = 100 nM) as 5-HT to inhibit the forskolin-stimulated adenylate cyclase in rat substantia nigra homogenates whereas this preferential 5-HT1B agonist was 100 times less potent than 5-HT in hippocampus guinea pig homogenates. Spiroperidol, mesulergine and ketanserin, which are potent 5-HT1A, 5-HT1C and 5-HT2 antagonists respectively, were unable to reverse the 5-HT-mediated inhibition of forskolin-stimulated adenylate cyclase whereas the beta-adrenoceptor antagonists, (+/-)-cyanopindolol and (+/-)-propranolol or metergoline, fully reversed the 5-HT effect with calculated Ki of 34 +/- 18, 82 +/- 19 and 248 +/- 47 nM, respectively. The pharmacological profile of the 5-HT receptor mediating the inhibition of adenylate cyclase in substantia nigra indicates that this receptor probably corresponds to 5-HT1B binding sites. Our conclusion is that, in addition to the 5-HT1A receptor, the 5-HT1B receptor is also negatively coupled to adenylate cyclase.
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PMID:5-HT1B receptors are negatively coupled with adenylate cyclase in rat substantia nigra. 297 54

The ability of 5-hydroxytryptamine (5-HT) and the 5-HT1A selective agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) to modulate adenylate cyclase activity was measured in rat hippocampus. In vitro ADP ribosylation of GTP-binding proteins by pertussis toxin in this tissue abolished both 5-HT- and 8-OH-DPAT-induced inhibition of forskolin-stimulated adenylate cyclase activity. These findings indicate that 5-HT1A receptors are linked a pertussis-sensitive Gi protein in rat hippocampus.
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PMID:5-Hydroxytryptamine1A receptors are linked to a Gi-adenylate cyclase complex in rat hippocampus. 297 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

The adenylate cyclase activator forskolin as well as 8-bromo-cyclic AMP enhanced the electrically evoked release of 3H-noradrenaline and 3H-5-hydroxytryptamine from superfused rat neocortical slices and that of 3H-dopamine from neostriatal slices with comparable EC50's of about 0.5 and 50 microM, respectively, without affecting spontaneous tritium efflux. The phosphodiesterase inhibitor ZK 62771 (3-100 microM) also enhanced 3H-noradrenaline and 3H-dopamine release but slightly reduced 3H-5-hydroxytryptamine release. However, this drug profoundly enhanced spontaneous tritium release in the latter case. The facilitatory effect of forskolin (0.3 microM) on the release of the amine neurotransmitters was potentiated in the presence of ZK 62771 (30 microM). Therefore, cyclic AMP appears to exert a general facilitatory effect on the release of these biogenic amines from central nerve terminals.
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PMID:Cyclic AMP facilitates the electrically evoked release of radiolabelled noradrenaline, dopamine and 5-hydroxytryptamine from rat brain slices. 299 41

A neuroblastoma X Chinese hamster embryonic brain explant hybrid cell line (NCB-20) expressed 5-hydroxytryptamine (5-HT1) receptors, linked to adenylate cyclase, which closely resembled 5-HT1 receptors previously characterized in central nervous tissue. However, the affinity of the receptors for 5-HT was only 150 nM compared to 5 nM in membranes prepared from cerebral cortex. The elevation of cyclic AMP levels in NCB-20 cells produced by 5-HT was found additive to that produced by cholera toxin but synergistic with that produced by either prostaglandin E1 (PGE1) or forskolin, suggesting that these latter two agents elevate cyclic AMP levels by a different mechanism than 5-HT. The elevation of cyclic AMP levels by either 5-HT or PGE1 was reversed by [D-Ala2,D-Leu5]enkephalin (DADLE), morphine, clonidine, and 3,4-dihydroxyphenylethylamine (dopamine) on a short (30 min) time scale. However, continued exposure to DADLE resulted in loss of the initial inhibitory effects of DADLE after 6 h and return of cyclic AMP levels to that seen with either 5-HT or PGE1 alone. When the DADLE exposure time was increased to 48 h, 5-HT produced a further twofold increase in cyclic AMP levels, but there was no increase in the responsiveness of the cells to PGE1 unless naloxone was added 1 h prior to treatment with PGE1. Scatchard analysis showed that the increased potency of 5-HT resulted from an increase in receptor affinity for 5-HT (from a KD of 150 +/- 20 nM to one of 20 +/- 7 nM), with a reduction in the number of apparent binding sites. The 5-HT supersensitivity observed in NCB-20 cells may be a good model for neurotransmitter interactions that produce desensitization or facilitation in the intact nervous system.
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PMID:Evidence for [D-Ala2,D-Leu5]enkephalin-induced supersensitivity to 5-hydroxytryptamine in a neurotumor x brain hybrid cell line (NCB-20). 299 93

Cultured NCB-20 hybrid cells express adenylate cyclase-coupled receptors for 5-hydroxytryptamine (5-HT) that correspond biochemically and pharmacologically to 5-HT1 receptors in rodent brain membrane preparations, apart from a much-reduced affinity for 5-HT (160 nM compared to less than 5 nM in brain). Since NCB-20 cells also differ from rodent brain both qualitatively and quantitatively in their ganglioside composition, the effects of exogenously added gangliosides on the affinity of the 5-HT1 receptor for 5-HT were tested. Both GM1 ganglioside (the cholera toxin receptor) and tetrasialoganglioside GQ1b produced a 10-fold increase in receptor affinity for [3H]5-HT, measured by binding studies. All gangliosides, at submicromolar concentrations, resulted in significantly reduced EC50 values for 5-HT-mediated elevation of intracellular cyclic AMP levels. GQ1b had the capacity to most dramatically enhance the potency of 5-HT in mediating increases in cyclic AMP levels. Gangliosides had no effect on the potency of DADLE or 3,4-dihydroxyphenylethylamine (dopamine)-mediated depression of cyclic AMP levels, suggesting some specificity for 5-HT. Our data are interpreted as implying a specific role for polysialogangliosides in modulating the affinity of the 5-HT1 receptor and the coupling of the 5-HT1 receptor-guanine nucleotide binding protein adenylate cyclase complex.
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PMID:Possible role of gangliosides in regulating an adenylate cyclase-linked 5-hydroxytryptamine (5-HT1) receptor. 299 94

The activation of human platelets by 5-hydroxytryptamine (5-HT) is not accompanied by detectable release of ATP or TXB2. The process is unaffected by cyclooxygenase, thromboxane synthetase or combined cyclooxygenase/lipoxygenase inhibition (suprofen, indomethacin, R 19091, dazoxiben, N.D.G.A, BW755C, esculetin), indicating the absence of involvement of arachidonic acid metabolites. Transmembrane Ca2+-entry blockers (flunarizine, nifedipine, nimodipine) have no effect either, indicating that the activator calcium released by 5-HT comes from intracellular stores. The 5-HT-induced platelet activation is inhibited by stimulators of adenylate cyclase (PGE1, PGE2, isoprenaline, adenosine) and inhibitors of cAMP phosphodiesterase (papaverine, anagrelide, RA233), indicating that also for this type of platelet activation cAMP behaves as a unidirectional, inhibitory regulator.
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PMID:Biochemical mechanisms in 5-hydroxytryptamine-induced human platelet aggregation. 300 59

Our previous results indicated that protein synthesis was necessary for serotonin (5-hydroxytryptamine, 5-HT) to regulate the phase of the biological clock in the Aplysia eye. Also, we showed that 5-HT appeared to increase the synthesis of a 34-kDa protein with an isoelectric point of 7.2. Subsequent studies were carried out to quantitate the effect of 5-HT on the 34-kDa protein and to examine whether the 34-kDa protein was involved in the circadian timing system. The regional specificity of the effect of 5-HT on the 34-kDa protein was investigated. The proximal portion of the eye appeared to synthesize much more of the 34-kDa protein than the distal portion. Also, 5-HT had a much larger effect on the synthesis of the 34-kDa protein in the proximal portion than in the distal portion. The proximal location of synthesis and the 5-HT effect on the synthesis of the 34-kDa protein correlate with the proximal location of cells and processes that are necessary for the expression of the circadian rhythm. The relationship between the effect of 5-HT on the circadian rhythm and the effect of 5-HT on the 34-kDa protein was also examined. As 5-HT causes phase shifts in the rhythm by activating adenylate cyclase to increase cAMP, forskolin and 8-benzylthioadenosine 3',5'-cyclic monophosphate mimicked the effect of 5-HT on the 34-kDa protein. We also found that 5-HT significantly increased the synthesis of the 34-kDa protein at phases when 5-HT delays or advances the phase of the rhythm but did not increase the synthesis of the 34-kDa protein at a phase when 5-HT did not phase shift. This phase-dependent effect of 5-HT on the 34-kDa protein qualitatively accounts for the phase dependence of the effect of 5-HT on the circadian rhythm. These results, when considered together with our earlier data, suggest that the synthesis of the 34-kDa protein is directly involved in the phase shift produced by 5-HT. The 34-kDa protein is worthy of future investigation as a candidate for a component of the circadian oscillator.
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PMID:Involvement of a specific protein in the regulation of a circadian rhythm in Aplysia eye. 302 61

Growth factors can be divided into two classes which act through distinct signal transduction pathways. One class including epidermal growth factor, platelet derived growth factor and fibroblast growth factor activates receptor tyrosine kinases, and the second class, including thrombin, bombesin, bradykinin and vasopressin activates a phosphoinositide-specific phospholipase C through GTP-binding proteins which can be inactivated by pertussis toxin. In Chinese hamster lung fibroblasts, thrombin-induced mitogenicity seems to correlate well with phospholipase C activation and both events are sensitive to pertussis toxin. Thrombin, like the other mitogens in this class, simultaneously inhibits adenylate cyclase. This involves an inhibitory G protein (Gi), a well established pertussis toxin substrate. The relative contributions of the two signalling pathways to mitogenicity has not been evaluated so far. We report here that the neurotransmitter serotonin (5-hydroxytryptamine), a contracting agent and mitogen for smooth muscle cells, activates phospholipase C, inhibits adenylate cyclase and stimulates DNA synthesis in fibroblasts. These events are sensitive to pertussis toxin. We show that the mitogenicity of 5-hydroxytryptamine can be uncoupled from phospholipase C activation that is mediated by 5-HT2 receptors, but correlates perfectly with inhibition of adenylate cyclase through 5-HT1B receptor. We propose that inhibition of adenylate cyclase or activation of an undefined effector system by Gi is important in 5-hydroxytryptamine induced DNA synthesis and contributes to the strong mitogenicity of the other members of this family of growth factors.
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PMID:Serotonin stimulates DNA synthesis in fibroblasts acting through 5-HT1B receptors coupled to a Gi-protein. 304 68


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