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)

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

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

5-HT binding sites of the 5-HT1 type are heterogeneous and appear to comprise several subtypes (5-HT1A, 5-HT1B and 5-HT1C); their physiological role is as yet unclear. The stimulation of adenylate cyclase induced by 5-HT has been investigated in membrane fractions prepared from rat brain cortex. Enzymatic activity was determined by measuring cAMP production with an HPLC technique. It was shown that 5-HT stimulates adenylate cyclase activity with 2 activation constants (Kact): one shows a high apparent affinity (Kact = 0.8 nM) and the other a lower apparent affinity (Kact = 0.30 microM). The latter activity, induced by micromolar concentrations of 5-HT, was inhibited by spiperone at concentrations that block 5-HT1A binding. 5-Methoxytryptamine, bufotenin, and LSD also had a stimulatory biphasic effect on adenylate cyclase activity, whereas trifluoromethylphenylpiperazine, 5-carboxyamidotryptamine, 8-hydroxy-(2-di-n-propylamino)tetralin, RU 24969 had a monophasic effect. Enzyme activation by drugs acting in the micromolar range was inhibited by spiperone (1 microM), suggesting a link between this activation and 5-HT1A sites. On the other hand, the high-affinity activation of the enzyme induced by 5-HT, 5-methoxytryptamine, bufotenin, LSD, and the activation induced by TFMPP were not inhibited by spiperone (1 microM), by propranolol (3 microM), or by mesulergine (0.1 microM), which selectively block 5-HT1A, 5-HT1B, and 5-HT1C sites. Inhibition was produced by dihydroergotamine, methysergide, cinanserin, and mianserin, but not by naloxone, phenoxybenzamine, and phentolamine. Therefore, these activations seem related to 5-HT1 receptors but not to 5-HT1A, 5-HT1B, or 5-HT1C sites. Accordingly, binding of [3H]5-HT to 5-HT1-like sites was examined in the presence of spiperone (1 microM) and propranolol (3 microM); in these conditions, a high-affinity site (KD = 3.4 nM) was indeed revealed. The relative potencies of a series of drugs that stimulate or inhibit the activation of the adenylate cyclase with a high affinity and their ability to inhibit this binding of [3H]5-HT showed a positive correlation, strongly suggesting a direct relation between this recognition site for 5-HT and the production of a second messenger (cAMP). Moreover, this potential receptor is shown to be heterogeneously distributed within the brain, and was localized postsynaptically at serotonergic synapses.
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PMID:5-Hydroxytryptamine stimulates two distinct adenylate cyclase activities in rat brain: high-affinity activation is related to a 5-HT1 subtype different from 5-HT1A, 5-HT1B, and 5-HT1C. 340 98

(E)-beta-Fluoromethylene-m-tyrosine (MDL 72394) is not per se an inhibitor of monoamine oxidase (MAO) but is a substrate of aromatic L-amino acid decarboxylase (AADC) which liberates the potent MAO inhibitor (E)-beta-fluoromethylene-m-tyramine (MDL 72392). When co-administered to animals with the peripherally selective AADC inhibitor, carbidopa, MDL 72394 inhibited MAO selectively in the brain. Chronic (14 days plus 3 days withdrawal) administration of 0.5 mg/kg per day p.o. MDL 72394, 0.1 mg/kg per day p.o. MDL 72394 combined with 10 mg/kg per day p.o. carbidopa or 50 mg/kg per day p.o. pargyline produced equivalent inhibition of rat brain MAO and decreased the binding of [3H]clonidine and [3H]RX 781094 to the alpha 2-adrenoceptor and of [3H]dihydroalprenolol to the beta-adrenoceptor without changing binding of [3H]prazosin to the alpha 1-adrenoceptor. The locomotor depressant effect of clonidine was attenuated without attenuation of the hypotensive effect in rats treated chronically with the MAO inhibitors. Neither the sensitivity of the alpha 2-autoreceptor nor of the alpha 2-heteroreceptor was decreased in brain slices. However, the sensitivity of adenylate cyclase to activation by both noradrenaline and isoprenaline was significantly reduced. The number of 5-HT2 and 5-HT1A binding sites was decreased: the 5-HT1B binding sites remained unchanged. The effect of chronic MAO inhibitor treatment on 5-HT1A receptors was associated with a decrease in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin and the decrease in 5-HT2 binding was related to a small reduction in the sensitivity of the inositol phosphate system to stimulation by 5-HT. The lack of effect of chronic MAO treatment on the 5-HT autoreceptor measured in cortical slices corresponded to a lack of effect on the 5-HT1B binding site except that chronic administration of pargyline produced a small but significant decrease in 5-HT autoreceptor sensitivity. Overall, the data show that chronic administration of MDL 72394 has a profile of effects on central monoamine receptor binding and function similar to that seen following chronic administration of a number of clinically effective antidepressants.
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PMID:Monoamine receptor sensitivity changes following chronic administration of MDL 72394, a site-directed inhibitor of monoamine oxidase. 378 Aug 61

5-HT receptors represent a superfamily of receptors with the largest known number of receptor subtypes. At present 15 receptor subtypes of three groups has been recognized. The 5-HT1 subfamily of receptors contains subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F; activation of all of them results in the inhibition of adenylylcyclase. The subfamily of 5-HT2 contains subtypes 5-HT2A, 5-HT2B, and 5-HT2C; their activation leads to the stimulation of PLC. Finally, subfamily of miscellaneous 5-HT receptors contains subtypes 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7; some of them has been cloned, however, our knowledge on their function is still minimal. 5-HT receptors participate in many physiological functions and a disturbance in serotonergic neurotransmission might cause several types of disease. 5-HT plays an important role in depression; to cure this disease, drugs which increase levels of this neurotransmitter are used. A new drug group called Selective Serotonin Reuptake Inhibitors (SSRI) has been recently discovered. These drugs block the reuptake of 5-HT into nerve endings. There is an intensive search for new selective agonists as well as antagonists which could be use not only in the classification of receptor subtypes but which also possess certain therapeutic potential.
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PMID:[5-hydroxytryptamine (serotonin) receptors--nomenclature and classification of types and subtypes]. 758 16

The functional activity of various 5-HT receptor agonists, including 5-CT, sumatriptan, CP 93, 129 and 1-naphtylpiperazine, and of drugs known to bind with high affinity to 5-HT1B (pindolol, propranolol, cyanopindolol, SDZ 21,009 and isamoltane) or 5-HT1D binding sites (yohimbine and rauwolscine) was measured at 5-HT receptors that are negatively coupled to adenylate cyclase in cultures of the renal epithelial cell line OK. 5-HT receptor-mediated inhibition of adenylate cyclase was studied by measuring inhibition of cAMP formation, induced by 100 microM forskolin. Besides 5-HT, various other compounds with affinity for 5-HT receptors behaved as agonists with the following rank order of potency: RU 24,969 > 5-CT > dihydroergotamine = 5-HT > CP 93,129 > d-LSD > 1-naphtylpiperazine > sumatriptan > TFMPP = mCPP > CGS 12066B = metergoline > methysergide. The beta-adrenergic receptor blockers cyanopindolol, SDZ 21,009, (-)-pindolol and (-)-propranolol, and the alpha 2-adrenergic blockers yohimbine and rauwolscine yielded agonist activity at nanomolar and micromolar concentrations, respectively. Isamoltane acted as a partial agonist. Methiothepin was the only compound that antagonised the OK cell 5-HT receptor-mediated inhibition of forskolin-induced cAMP formation. We conclude that the OK cell 5-HT receptor has properties consistent with a 5-HT1B receptor, although differences are apparent with regard to potencies of some compounds. Methiothepin is probably the only effective antagonist at 5-HT1B receptor sites, whereas the described putative 5-HT1B receptor antagonists have to be considered as partial agonists, yielding agonist or antagonist activity depending on the system that is studied.
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PMID:Inhibition by 5-HT of forskolin-induced cAMP formation in the renal opossum epithelial cell line OK: mediation by a 5-HT1B like receptor and antagonism by methiothepin. 791 Mar 88

The influence of chronic administration of desipramine (16 mg/kg per day for 8 days) or citalopram (1 mg/kg per day for 8 days) on the serotonergic and noradrenergic stimulations of phosphoinositide hydrolysis and cyclic AMP formation was investigated in rat cerebral cortical slices. This was done by means of a prelabelling method allowing the simultaneous measurement of the accumulations of (3H) inositol phosphates ((3H)IP) and of (14C) cyclic AMP. Our results show that neither of the two drugs altered the inhibition of adenylate cyclase activity induced by serotonin1 (5-HT1) receptor agonists nor did they alter 5-HT1A and 5-HT1B receptor densities. Similarly they did not modify the stimulation of the inositol phosphate metabolism induced by 5-HT or norepinephrine (NE). Desipramine treatment decreased both beta-adrenoceptor-elicited cyclic AMP accumulation (-37%) and beta-adrenoceptor density (-29%), whereas citalopram was without effect. These results reinforce the idea that the ability of antidepressants to decrease the activity of the beta-adrenoceptor-adenylate cyclase complex is not common to all antidepressants, and provide no evidence for the involvement of 5-HT1A and/or 5-HT1B in the mechanism of action of these drugs.
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PMID:Cyclic AMP and inositol phosphate accumulations in rat brain cortical slices following chronic citalopram or desipramine administration. 795 21

The pharmacological properties of SDZ 216-525, methyl 4-(4-[4-(1,1,3-trioxo-2H-1,2-benzoisothiazol-2-yl)butyl]-1-p iperazinyl)1H- indole-2-carboxylate, a new selective and potent 5-HT1A receptor antagonist, are described in vitro (and comparisons made with those of MDL 73005 and NAN 190, two putative 5-HT1A receptor antagonists) and in vivo. In radioligand binding studies, SDZ 216-525 showed high affinity and selectivity for 5-HT1A sites (pKD = 9.2) as compared to 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3 sites (pKD = 6.0, 7.2, 7.5, 5.2 and 5.4, respectively). The affinity of the compound for alpha 1, alpha 2, beta 1 and beta 2 adrenoceptors, and dopamine D2 receptors was at least 50-100 times lower than for 5-HT1A sites. The effects of SDZ 216-525, MDL 73005 and NAN 190 on 5-HT1 receptor-linked second messengers were characterised in the following tests: inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus (5-HT1A), rat substantia nigra (5-HT1B) and calf substantia nigra (5-HT1D) and stimulation of inositol phosphate production in pig choroid plexus (5-HT1C). SDZ 216-525 potently antagonised the effects of 8-OH-DPAT (8-hydroxy-2-[N-dipropyl-amino]-tetralin) on 5-HT1A receptors (pKB = 10) and displayed no intrinsic activity in this test, whereas it behaved at best as a weak antagonist on the other receptor models (pKB values < 6.9).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:SDZ 216-525, a selective and potent 5-HT1A receptor antagonist. 838 69

Sequential polymerase chain reaction experiments were performed to amplify a unique sequence representing a guanine nucleotide-binding protein (G-protein)-coupled receptor from rat hypothalamic cDNA. Degenerate oligonucleotides corresponding to conserved amino acids from transmembrane domains III, V, and VI of known receptors [5-HT1A, 5-HT1C, and 5-HT2; 5-HT is serotonin (5-hydroxytryptamine)] were used as primers for the sequential reactions. The resulting product was subcloned and used to screen a rat genomic library to identify a full-length clone (MR77) containing an intronless open reading frame encoding a 366-amino acid seven-transmembrane domain protein. The human homolog was isolated, and its encoded protein had 93% overall amino acid identity with the rat sequence. Within the conserved transmembrane domains, the sequences exhibit approximately 52%, 59%, 65%, and 68% amino acid identity with the known rat 5-HT1A, rat 5-HT1B, rat 5-HT1D, and human 5-HT1E receptors, respectively. MR77 was subcloned into a eukaryotic expression vector system and expressed in CosM6 cells. Studies on broken cell preparations indicate that the expressed receptor exhibits 125I-labeled d-lysergic acid diethylamide (LSD) binding that can be displaced by serotonin but not by other biogenic amines. The specific binding is displaced by the selective 5-HT1D agonist sumatriptan but not by the mixed 5-HT1A/1D agonist 5-carboxyamidotryptamine. 125I-labeled LSD binding was competitively antagonized by the ergot alkaloids methysergide and ergotamine. HeLa cells transfected with the MR77 gene exhibited inhibition of adenylate cyclase in response to serotonin. MR77 is expressed at low levels throughout the brain, with the greatest expression in the cortex, hippocampus, and striatum. MR77 thus represents a 5-HT receptor of the 5-HT1 class, and we propose that, based on the pharmacological characterization, MR77 represents an additional 5-HT1E-like receptor.
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PMID:Molecular cloning and functional expression of 5-HT1E-like rat and human 5-hydroxytryptamine receptor genes. 838 16

The serotonin (5-HT) receptor subtype mediating inhibition of neurogenic dural inflammation in guinea pigs was investigated using a series of serotonin agonists with differing affinities for the 5-HT1B, 5-HT1D and 5-HT1F receptors. When agonist potencies for inhibiting neurogenic inflammation were compared with affinities for these receptor subtypes, a significant positive correlation was seen only with the 5-HT1F receptor. The potency of agonists in inhibiting adenylate cyclase in cells transfected with human 5-HT1F receptor was also highly correlated with their potency in the animal model of migraine. In situ hybridization demonstrated 5-HT1F receptor mRNA in guinea pig trigeminal ganglion neurons. These data suggest that the 5-HT1F receptor is a rational target for migraine therapeutics.
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PMID:5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs. 924 18


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