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 5-hydroxytryptamine (5-HT) receptor agonists on calcium (Ca2+)-stimulated adenylate cyclase activity in the hippocampus and cerebral cortex of the rat were studied. In the presence of Ca2+ (1.5 microM), 5-HT dose dependently inhibited adenylate cyclase activity (EC50 = 10 +/- 2 nM). The inhibitory effect of 5-HT on Ca2(+)-stimulated adenylate cyclase was antagonized by spiperone (KB = 2 +/- 0.8 nM). The rank order of potency of 5-HT agonists to inhibit Ca2(+)-stimulated adenylate cyclase in the hippocampus was: 5-carboxamidotryptamine (5-CT) greater than 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) greater than 5-hydroxytryptamine (5-HT) = 5-methoxytryptamine (5-OCH3-T) greater than trifluoromethylphenylpiperazine (TFMPP) greater than m-chlorophenylpiperazine (mCPP). 2-Methyl-5-hydroxytryptamine (2-CH3-5-HT) did not exert an effect on Ca2(+)-stimulated enzyme activity. In the cerebral cortex 5-HT exerted a biphasic stimulatory effect on adenylate cyclase activity in the absence of Ca2+ (EC50 = 0.2 +/- 0.04 nM and 10 +/- 3 microM), whereas 8-OH-DPAT, 5-CT and 2-CH3-5-HT exerted a monophasic effect. In the presence of Ca2+ (1.5 microM), low concentrations of 5-HT, 8-OH-DPAT, 5-CT and 2-CH3-5-HT potentiated adenylate cyclase activity, whereas higher concentrations, except 2-CH3-5-HT, inhibited the enzyme activity. We propose that the 5-HT receptor mediating inhibition of Ca2(+)-stimulated adenylate cyclase in the rat hippocampus corresponds to the 5-HT1A subtype.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Hydroxytryptamine receptor agonists influence calcium-stimulated adenylate cyclase activity in the cerebral cortex and hippocampus of the rat. 213 81

Serotonin (5-hydroxytryptamine) (5HT) a neurotransmitter and vasoactive amine, is a major storage product of platelets that are released at sites of inflammation. Several different subtypes of serotonin receptors have been defined. 5HT receptors have been divided into three major families based on molecular, biochemical, and pharmacologic properties. Binding of serotonin to the 5HT1 family results in inhibition of adenylate cyclase whereas binding to the 5HT2 family results in stimulation of phosphatidylinositol turnover and mobilization of intracellular Ca2+. 5HT has been shown to have effects on lymphoid cells. The question of whether human T lymphocytes express receptors for 5HT and transduce signals through 5HT receptors has not been adequately addressed. As a model system, Jurkat cells (a transformed human T lymphocyte line) were examined to determine if they expressed 5HT receptors and whether 5HT stimulated an increase in inositol phosphates or affected adenylate cyclase activity. The results show that Jurkat cells bind 5HT with an average dissociation constant of 90 nM and that 5HT stimulates an increase in inositol phosphate and intracellular Ca2+ levels. These results link the 5HT receptor on Jurkat cells to the 5HT2 family; however, studies with 5HT receptor agonists and antagonists failed to clearly classify the 5HT receptor on Jurkat cells as a known member of the 5HT2 family.
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PMID:Serotonin-activated signal transduction via serotonin receptors on Jurkat cells. 214 10

In pigs, behavioural responses were examined after administration of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a full agonist at 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype, and the pyrimidinylpiperazine derivatives ipsapirone and Bay Vq 7813 (2-[4-(2-pyrimidinyl)-1-piperazinylpropyl]-1,2-benzisothiazol++ +-3(2H) one-1,1-dioxide), which act as partial agonists at 5-HT1A receptors. The most prominent behavioural response examined after 8-OH-DPAT, 0.5 mg/kg i.m., ipsapirone, 2-5 mg/kg i.m., and Bay Vq 7813, 0.5-2 mg/kg i.m. or i.v., were head shakes. The potency of the three drugs to induce this behaviour correlated with their activity at 5-HT1A receptors as determined by inhibition of forskolin-stimulated adenylate cyclase, substantiating that the head shake response has potential as a quantitative probe of in vivo receptor function. The 5-HT2/5-HT1C receptor antagonist ritanserin did not counteract the head shakes induced by ipsapirone, suggesting that neither 5-HT2 nor 5-HT1C receptors are involved in mediation of this response to this 5-HT1A receptor agonist in pigs. Once daily administration of Bay Vq 7813 or ipsapirone for 3-5 days led to a reduction in the head shake response. 1-Pyrimidinylpiperazine (1-PP), a pharmacologically active metabolite shared by ipsapirone, Bay Vq 7813, and related pyrimidinylpiperazine derivatives, did not induce behavioural alterations in pigs. The data provide further evidence that marked species differences exist in functional responses to 5-HT receptor ligands.
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PMID:The behavioural responses to 8-OH-DPAT, ipsapirone and the novel 5-HT1A receptor agonist Bay Vq 7813 in the pig. 214 68

Permanent clonal cell lines from newborn mouse striatum have been established after transfer of the simian virus 40 large tumor oncogene by means of a retroviral vector. Some of the lines obtained displayed properties of bipotential and plastic glio-neuronal precursors. Depending on the culture conditions, these cells express either the glial fibrillary acidic protein or neurofilaments. In addition, the cells can display adrenergic, D1 and D2 dopaminergic, muscarinic, and 5-hydroxytryptamine type 2 serotoninergic receptors, which are coupled either to the adenylate cyclase or to the phosphatidylinositol signaling pathways. The panel of receptors for neurotransmitters exhibited by these lines closely resembles that of primary striatal neurons. Results suggest that plastic common precursors of astrocytes and neurons persist in the striatum at a late developmental stage. As these permanent cell lines constitute an unlimited source of homogenous cell material, we suggest that they should be useful for molecular and pharmacological studies on the mechanisms and regulation of signal transduction as well as the commitment, plasticity, and differentiation of neural cells.
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PMID:Immortalization of bipotential and plastic glio-neuronal precursor cells. 215 1

Sumatriptan (GR43175) contracts rings of dog isolated saphenous vein by an action at 5-HT1-like receptors. We have now examined the effects of sumatriptan on prostaglandin E2(PGE2)-stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation in this tissue. Sumatriptan and 5-hydroxytryptamine (5-HT) produced a concentration-dependent inhibition of PGE2-stimulated cyclic AMP accumulation (EC50 values of 250 nM and 80 nM respectively), responses that were mimicked by 5-carboxamidotryptamine but not by U-46619 or methoxamine. The response to sumatriptan (1 microM) was antagonised by methiothepin (1 microM), but not by metergoline (0.1 microM), spiperone (1 microM) or ondansetron (GR38032, 1 microM). These results suggest that 5-HT1-like receptors which mediate contraction of the dog isolated saphenous vein are negatively coupled to adenylate cyclase in this preparation.
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PMID:Sumatriptan (GR43175) inhibits cyclic-AMP accumulation in dog isolated saphenous vein. 215 69

The mandibular closer muscles of the locust receive innervation that is immunoreactive for the putative transmitter 5-hydroxytryptamine (5-HT). Cobalt-labelling suggests that the origin of this innervation is a group of cells located anteriorly in the suboesophageal ganglion. Bath application of 5-HT while the muscles are active produces marked changes in the contractions, increasing their amplitude, rate of contraction, and rate of relaxation. Incubation of isolated muscles with 5-HT shows that this amine elevates the levels of the cyclic nucleotide cyclic adenosine monophosphate (cAMP). In addition compounds that artificially elevate the levels of cAMP in the muscle--3-isobutyl-1-methylxanthine (IBMX), forskolin, and the cAMP analogue 8-(4-chlorophenylthio) cAMP--mimic the actions of 5-HT, whereas a potent inhibitor of insect adenylate cyclase, adenosine, considerably delays the onset of the effects produced by 5-HT. The effects observed with 5-HT in the mandibular muscle are similar to those of octopamine in the locust extensor tibiae muscle, and it is possible that this is an analogous modulatory system.
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PMID:Serotoninergic innervation of the locust mandibular closer muscle modulates contractions through the elevation of cyclic adenosine monophosphate. 216 Apr 81

Eicosanoids have been shown to be important modulators of intestinal secretion. In cholera, cAMP is often regarded as the sole mediator, but recent data suggest that 5-hydroxytryptamine (5-HT) and prostaglandin (PG) E2 also play important roles. Thus cholera toxin (CT) increases their release from the rat jejunum in vivo, and human cholera is associated with an increased luminal 'overflow' of PGE2. In vitro evidence of secretion can be obtained with PG concentrations 100- to 1000-fold lower than those required for activation of the adenylate cyclase. Furthermore, 5-HT induces secretion associated with increased 'overflow' of PGE2, but without a change in mucosal cAMP. CT-induced release of PGE2 and fluid secretion can be decreased by indomethacin or by the 5-HT2-receptor antagonist, ketanserin, whereas the release of 5-HT and cAMP is not affected by either substance. Secretion caused by vasoactive intestinal polypeptide (VIP) is associated with increased mucosal cAMP levels, without a change in PGE2 release, and is unaffected by indomethacin and ketanserin. These results suggest that CT stimulates the release of 5-HT, which in turn causes the release of PGE2. The latter substances probably act via a local intramural reflex and contribute to secretion by mechanisms that are independent of cAMP.
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PMID:Influence on intestinal secretion of eicosanoids. 216 23

Melatonin binding sites were localized and characterized in the vasculature of the rat by using the melatonin analogue 2-[125I]iodomelatonin (125I-melatonin) and quantitative in vitro autoradiography. The expression of these sites was restricted to the caudal artery and to the arteries that form the circle of Willis at the base of the brain. The arterial 125I-melatonin binding was stable, saturable, and reversible. Saturation studies revealed that the binding represented a single class of high-affinity binding sites with a dissociation constant (Kd) of 3.4 x 10(-11) M in the anterior cerebral artery and 1.05 x 10(-10) M in the caudal artery. The binding capacities (Bmax) in these arteries were 19 and 15 fmol/mg of protein, respectively. The relative order of potency of indoles for inhibition of 125I-melatonin binding at these sites was typical of a melatonin receptor: 2-iodomelatonin greater than melatonin greater than N-acetylserotonin much much greater than 5-hydroxytryptamine. Norepinephrine-induced contraction of the caudal artery in vitro was significantly prolonged and potentiated by melatonin in a concentration-dependent manner, suggesting that these arterial binding sites are functional melatonin receptors. Neither primary steps in smooth muscle contraction (inositol phospholipid hydrolysis) nor relaxation (adenylate cyclase activation) were affected by melatonin. Melatonin, through its action on the tone of these arteries, may cause circulatory adjustments in these arteries, which are believed to be involved in thermoregulation.
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PMID:Expression of melatonin receptors in arteries involved in thermoregulation. 216 49

Adult guinea pig hippocampal membranes contain two 5-hydroxytryptamine (5-HT) receptors positively coupled with an adenylate cyclase. One is a typical 5-HT1A receptor and the second is a nonclassical 5-HT receptor that we previously proposed to call 5-HT4. Here, we show that 4-amino-5-chlor-2-methoxy-benzamide derivatives are agonists of 5-HT4 receptors in guinea pig hippocampal membranes. Their effects on the adenylate cyclase of these membranes are not additive with those of 5-HT but are additive with those of RU 24969, a typical 5-HT1 agonist. The effects of benzamides, as well as those of 5-HT, on 5-HT4 receptors are not blocked by 5-HT1, 5-HT2, or 5-HT3 antagonists except ICS 205 903, which does so with a low affinity (1 microM). The potency of benzamides (cisapride greater than BRL 24924 greater than zacopride greater than BRL 20627 greater than metoclopramide) is similar to their effect of 5-HT4 receptors positively coupled with an adenylate cyclase of fetal mouse colliculi neurons.
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PMID:Pharmacological characterization of 5-hydroxytryptamine4(5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives. 231 90

Serotonin (5-hydroxytryptamine; 5-HT) and its analogs activate adenylate cyclase in membrane particles from neuroblastoma NCB.20 cells. Low concentrations of GTP (EC50 = 60 nM) were required for activation by serotonin. Guanosine 5'-O-(2-thiodiphosphate) inhibited serotonin-activated cyclase in these cells. The nonhydrolyzable GTP analogs guanosine 5'-O-(3-thiotriphosphate) (EC50 = 3 nM) and guanylyl-imidodiphosphate (EC50 = 100 nM) substituted for GTP in potentiating serotonin activation. Pretreatment of the cells with cholera toxin potentiated enzyme activation by serotonin, whereas pertussis toxin was found to have little effect, indicating the involvement of the alpha subunit of a stimulatory GTP-binding protein in enzyme activation. Homologous desensitization of the serotonin-stimulated adenylate cyclase was demonstrated in membranes prepared from intact cells pretreated with serotonin. Cell membrane particles that were desensitized to serotonin were still responsive to beta-adrenergic agonists and to prostaglandin E1. Evidence is presented indicating that serotonin stimulation of adenylate cyclase is mediated by receptors that are distinct from other positively coupled receptors (beta-adrenergic, histamine, and prostacyclin). Equilibrium binding analysis with [3H]serotonin, [3H]lysergic acid diethylamide, and [3H]dihydroergotamine suggested that the site density was below the level of detection of binding of these radioligands. The pharmacological characteristics of the serotonin-activated cyclases were analyzed in order to compare these serotonin receptors with the family of different receptor subtypes. Correlation analysis between the potencies of different agonists and antagonists at the cyclase in these cells and their reported relative potencies for different serotonin receptor subtypes showed no correlation with the 5-HT1A, 5HT1B, 5HT1D, 5-HT2, and 5-HT3 receptors. On the other hand, the analysis showed that the NCB.20 serotonin receptors are similar but not identical to the rat and pig brain 5-HT1C receptors and to the serotonin receptors coupled to adenylate cyclase in the trematodes Schistosoma mansoni and Fasciola hepatica. The results point to a novel serotonin receptor which has a low density in these cells.
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PMID:Serotonin receptor-mediated activation of adenylate cyclase in the neuroblastoma NCB.20: a novel 5-hydroxytryptamine receptor. 233 46


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