Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Grease-gap recordings revealed that 5-hydroxytryptamine (5-HT) depolarized the ferret vagus nerve (pEC50 = 4.9). This response was mimicked by 2-methyl-5-HT and 1-phenylbiguanide, but not by 5-carboxamidotryptamine. Paroxetine (1 microM) or ketamine (10 microM) did not potentiate the response. Ketanserin (1 microM) did not reduce the depolarization, but four 5-HT3 receptor antagonists did. It is concluded that 5-HT depolarizes the ferret vagus nerve via 5-HT3 receptors, but these receptors may differ pharmacologically from those in other species.
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PMID:Pharmacology of the 5-hydroxytryptamine-induced depolarization of the ferret vagus nerve in vitro. 145 88

The 5-hydroxytryptamine (5-HT)3 receptor blocking properties of YM060, [(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole hydrochloride], were examined by electrophysiological and radioligand binding studies. Results were compared with those for ondansetron, granisetron and the enantiomer (S-form) of YM060. 5-HT and 2-methyl-5-HT, a selective 5-HT3 receptor agonist, induced dose-dependent depolarizations of rabbit nodose ganglion with ED50 values of 24.0 (19.9-29.1) and 40.1 (30.9-52.1) nmol, respectively (geometric mean, 95% CL). YM060, ondansetron, granisetron and the S-form dose-dependently inhibited 5-HT-induced depolarizations with IC50 values of 3.85 (2.47-5.98), 1.55 (1.26-1.91), 1.45 (1.18-1.79) and 13.5 (11.2-16.2) nM, respectively. Methysergide, a 5-HT1-like and 5-HT2 receptor antagonist, at a concentration of 10(-5) M had no effect on responses to 5-HT. YM060 up to 10(-5) M produced no significant depression of depolarizing responses to 1,1-dimethyl-4-phenylpiperazinium iodide and gamma-aminobutyric acid. YM060, ondansetron, granisetron and the S-form displaced specific binding of [3H]GR65630 to N1E-115 neuroblastoma cell membranes with Ki values of 0.091 (0.086-0.097), 7.03 (5.96-8.01), 2.02 (1.74-2.30) and 10.3 (9.96-10.6) nM, respectively. These results show that YM060, compared with ondansetron and granisetron, has considerably higher affinity for 5-HT3 receptors in N1E-115 cells and slightly less potent 5-HT3 receptor antagonistic activity in rabbit nodose ganglion. Moreover, the isomeric activity ratio (R-form/S-form) was approximately 112 in N1E-115 cells and no greater than 4 in the ganglion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of YM060, a potent and selective 5-hydroxytryptamine3 receptor antagonist, in rabbit nodose ganglion and N1E-115 neuroblastoma cells. 146 24

Intracellular recording methods were used to study the actions of 5-hydroxytryptamine (5-HT) on 257 myenteric neurons in the guinea pig gastric antrum. Application of 5-HT caused three types of postsynaptic responses. A fast-activating depolarizing response was accompanied by a decreased input resistance and desensitized quickly to repeated applications. It was mediated by a 5-HT3 receptor. A slowly activating depolarization, accompanied by an increase in the input resistance and enhancement of the excitability, was mainly observed in after hyperpolarizing/type 2 neurons. It was suppressed by the prokinetic benzamide compound renzapride, while classical 5-HT1-4 receptor antagonists had no effect, suggesting the involvement of a 5-HT1p receptor as described in small intestinal neurons. A long-lasting hyperpolarizing response, accompanied by a decreased input resistance, was observed in a small subset of neurons. This response seemed to be mediated by a 5-HT1a receptor. Superfusion of 5-HT caused a dose-dependent inhibition of the stimulus-evoked nicotinic cholinergic fast excitatory postsynaptic potential (EPSP), which was mediated by a presynaptic 5-HT1a receptor. 5-HT also presynaptically inhibited the slow EPSP.
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PMID:Actions of 5-hydroxytryptamine on myenteric neurons in guinea pig gastric antrum. 147 91

1. Intracerebral microdialysis was used to determine whether 5-hydroxytryptamine (5-HT) release in the ventral hippocampus of rats anaesthetized with chloral hydrate was modulated by 5-HT3 receptors. 2. It was confirmed that 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), a selective 5-HT1B receptor agonist, decreased 5-HT release in a dose- and concentration-related manner when administered i.p. (1 and 5 mg kg-1) or via the dialysis probe (0.1 and 1 microM) respectively. The effect of RU 24969 infusion (1 microM) was attenuated by concurrent infusion of metitepine (10 microM) into the hippocampus. 3. When infused into the hippocampus for 15 min, the selective 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT; 0.1- 10 microM) increased dialysate 5-HT levels in a concentration-related manner; an effect which was abolished by concurrent infusion of 3-tropanyl-3,5-dichlorobenzoate (1 microM, MDL 72222), a selective 5-HT3 antagonist. 4. MDL 72222 had no effects on hippocampal 5-HT release when administered via the dialysis probe (1 or 10 microM). 5. The data show that 5-HT3 and 5-HT1B receptors have opposing roles in the control of 5-HT release in the hippocampus, with 5-HT3 receptors facilitating and 5-HT1B receptors inhibiting 5-HT efflux, respectively. They also indicate that the facilitatory 5-HT3 receptors are not tonically activated.
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PMID:Opposing roles for 5-HT1B and 5-HT3 receptors in the control of 5-HT release in rat hippocampus in vivo. 150 23

1. Tritiated derivatives of the potent and selective 5-HT3 receptor antagonists GR65630 and LY278584 were used to identify 5-HT3 recognition sites in the rat gastrointestinal tract. 2. Binding studies were carried out in homogenates of the rat oesophagus, the cardia, fundus, body and antrum of the stomach, regions of the small intestine, caecum and large intestine. The specific binding of a single concentration of GR65630 (0.5 nM) defined by granisetron (10 microM) in these areas indicated that the density of 5-HT3 recognition sites varied from 2.4 +/- 1.0 to 10.1 +/- 1.0 fmol mg-1 protein. 3. Saturable binding of [3H]-GR65630 could only be demonstrated in the terminal regions of the small intestine (Bmax in the range of 13.83 +/- 4.54-21.19 +/- 0.89 fmol mg-1 protein; mean +/- s.e. mean) and of high affinity (Kd in the range of 0.42 +/- 0.18-0.79 +/- 0.24 nM). Use of [3H]-LY278584 revealed a similar binding density (Bmax 19.54 +/- 0.26 fmol mg-1 protein) and affinity (Kd 1.04 +/- 0.07 nM) in the terminal small intestine. 4. Binding of [3H]-GR65630 and [3H]-LY278584 to the terminal region of the small intestine was inhibited by 5-HT3 receptor ligands ondansetron and S-zacopride (and 5-hydroxytryptamine), but not by 5-HT1, 5-HT2, catecholamine, gamma-aminobutyric acid and opioid receptor ligands. 5. These data demonstrate that there are regional variations in the density of 5-HT3 recognition sites within the rat gastrointestinal tract. Such data are relevant to the potential use of 5-HT3 receptor ligands to modify secretory and contraction responses in the gastrointestinal system.
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PMID:Identification and distribution of 5-HT3 recognition sites in the rat gastrointestinal tract. 150 52

The study concerned the effects of 5-hydroxytryptamine (5-HT) on intragastric pressure in bilaterally vagotomized spinal rats. Intravenous (i.v.) bolus injections of 5-HT (2.5, 5.0 and 10 micrograms/kg) produced dose-dependent increases in intragastric pressure; these effects were not modified by atropine (up to 0.2 mg/kg) or mepyramine (1 mg/kg), but were blocked by the mixed 5-HT1-like and 5-HT2 receptor antagonists, methiothepin (0.1, 0.3 and 0.5 mg/kg i.v.) and methysergide (0.5, 1 and 2.5 mg/kg i.v.). However, metergoline (0.5, 1 and 2 mg/kg i.v.) did not markedly modify this effect of 5-HT; only the response induced by 5 micrograms/kg 5-HT was significantly antagonized by the highest dose of metergoline. In contrast, neither the 5-HT2 receptor antagonist, ketanserin (0.5, 1 and 1.5 mg/kg i.v.), nor the 5-HT3 receptor antagonist, ICS 205-930 (0.5, 1 and 3 mg/kg i.v.), influenced the 5-HT-induced increase in intragastric pressure. In addition, 5-carboxamidotryptamine (25, 50 and 100 micrograms/kg i.v.) and RU 24969 (50, 100 and 200 micrograms/kg i.v.) mimicked the aforementioned effects of 5-HT but were weaker than 5-HT. These data suggest that the 5-HT-induced increase in intragastric pressure in the spinal and bilaterally vagotomized rat is mediated by an atypical 5-HT1-like receptor, which, based on the low agonist potency of 5-carboxamidotryptamine and RU 24969 and the resistance to blockade by metergoline, does not seem to correspond to either the 5-HT1A, 5-HT1B, 5-HT1C or the 5-HT1D receptor subtypes.
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PMID:Role of 5-HT1-like receptors in the increase in intragastric pressure induced by 5-hydroxytryptamine in the rat. 152 63

To improve the pharmacological characterization of the receptors mediating 5-hydroxytryptamine (5-HT)-induced apnea the inhibitory effects of exogenous 5-HT on respiration and phrenic nerve activity (PNA) were studied in anesthetized rats. The effects of putative 5-HT receptor agonists and antagonists on respiratory parameters were examined. During spontaneous respiration the bolus i.v. injection of 5-HT (3.125-25 micrograms/kg) produced a transient apnea, the duration of which increased in a dose-related manner. In addition, during artificial respiration 5-HT produced a silent response of PNA, the duration of which increased dose-dependently. These responses were significantly antagonized by GR38032F, a selective 5-HT3 receptor antagonist. Ketanserin (100 micrograms/kg) and methysergide (100 micrograms/kg), 5-HT2 receptor antagonists, also inhibited the 5-HT-induced apnea. These effects of 5-HT on respiration were mimicked by 2-methyl-5-HT (3.125-25 micrograms/kg), a selective 5-HT3 receptor agonist, and by a high dose of alpha-methyl-5-HT, a 5-HT2 receptor agonist, but not by 5-carboxamidotryptamine, a 5-HT1-like receptor agonist. Lung compliance was greatly reduced and lung resistance greatly increased by 5-HT (3.125-25 micrograms/kg). The 5-HT-induced changes in lung compliance and lung resistance were antagonized markedly by both ketanserin (100 micrograms/kg) and methysergide (100 micrograms/kg), but not by GR38032F (100 micrograms/kg). Bilateral vagotomy above the nodose ganglia completely prevented both the changes in PNA and the apnea induced by 5-HT. These actions of 5-HT were not prevented, however, by cervical vagotomy below the level of the nodose ganglion. On the other hand, this cervical vagotomy completely blocked the alpha-methyl-5-HT-induced apnea.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological characterization of 5-hydroxytryptamine-induced apnea in the rat. 153 63

Synaptosomes prepared from freshly obtained human cerebral cortex and labeled with [3H]choline have been used to investigate the modulation of [3H]acetylcholine ([3H]ACh) release by 5-hydroxytryptamine (5-HT). The Ca(2+)-dependent release of [3H]-ACh occurring when synaptosomes were exposed in superfusion to 15 mM KCl was inhibited by 5-HT (0.01-1 microM) in a concentration-dependent manner. The effect of 5-HT was mimicked by 1-phenylbiguanide, a 5-HT3 receptor agonist, but not by 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-HT1A receptor agonist. The 5-HT3 receptor antagonists tropisetron and ondansetron blocked the effect of 5-HT, whereas spiperone and ketanserin were ineffective. It is suggested that cholinergic axon terminals in the human cerebral cortex possess 5-HT receptors that mediate inhibition of ACh release and appear to belong to the 5-HT3 type.
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PMID:5-Hydroxytryptamine3 receptors sited on cholinergic axon terminals of human cerebral cortex mediate inhibition of acetylcholine release. 153 19

1. The pharmacological properties of 5-HT3 receptor recognition sites labelled with [3H]-(S)-zacopride, [3H]-LY278,584, [3H]-granisetron and [3H]-GR67330 in membranes prepared from the rat entorhinal cortex were investigated to assess the presence of cooperativity within the 5-HT3 receptor complex. 2. In rat entorhinal cortex homogenates, [3H]-(S)-zacopride, [3H]-LY278,584, [3H]-granisetron and [3H]-GR67330 labelled homogeneous densities of recognition sites (defined by granisetron, 10 microM) with high affinity (Bmax = 75 +/- 5, 53 +/- 5, 92 +/- 6 and 79 +/- 6 fmol mg-1 protein, respectively; pKd = 9.41 +/- 0.04, 8.69 +/- 0.14, 8.81 +/- 0.06 and 10.14 +/- 0.04 for [3H]-(S)-zacopride, [3H]-LY278,584, [3H]-granisetron and [3H]-GR67330, respectively, n = 3-8). 3. Quipazine and granisetron competed for the binding of each of the radioligands in the rat entorhinal cortex preparation at low nanomolar concentrations (pIC50; quipazine 9.38-8.51, granisetron 8.62-8.03), whilst the agonists, 5-hydroxytryptamine (5-HT), phenylbiguanide (PBG) and 2-methyl-5-HT competed at sub-micromolar concentrations (pIC50; 5-HT 7.16-6.42, PBG 7.52-6.40, 2-methyl-5-HT 7.38-6.09). 4. Competition curves generated with increasing concentrations of quipazine, PBG, 5-HT and 2-methyl-5-HT displayed Hill coefficients greater than unity when the 5-HT3 receptor recognition sites in the entorhinal cortex preparation were labelled with [3H]-LY278,584, [3H]-granisetron and [3H]-GR67330. These competing compounds displayed Hill coefficients of around unity when the sites were labelled with [3H]-(S)-zacopride. Competition for the binding of [3H]-(S)-zacopride, [3H]-LY278,584, [3H]-granisetron and [3H]-GR67330 by granisetron generated Hill coefficients around unity.5. The nature of the interaction of competing compounds (quipazine, granisetron, PBG, 5-HT, 2-methyl-5-HT) for the [3H]-(S)-zacopride binding site in the rat entorhinal cortex preparation was not altered by the removal of the Krebs ions or the addition of the monoamine oxidase inhibitor, pargyline, to the HEPES/Krebs buffer.6. In conclusion, the present studies provide further evidence towards the presence of cooperativity within the 5-HT3 receptor macromolecule and indicate that either [3H]-(S)-zacopride labels a different site on the receptor complex from [3H]-LY278,584, [3H]-granisetron or [3H]-GR67330, or it binds in such a manner as to prevent the conformatory change in the receptor protein responsible for the cooperative binding of agonists (and quipazine).
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PMID:Agonist interactions with 5-HT3 receptor recognition sites in the rat entorhinal cortex labelled by structurally diverse radioligands. 155 39

The influence of three azabicycloalkyl benzimidazolone derivatives, DAU 6236, BIMU 1 and BIMU 8, which act as agonists at central 5-hydroxytryptamine (5-HT)4 receptors, has been investigated on cholinergic neuromuscular transmission and peristalsis in the guinea pig small intestine. In the longitudinal muscle myenteric plexus preparations, these compounds caused a concentration-dependent (range 1-300 nM) enhancement of the amplitude of nerve-mediated cholinergic submaximal contractions to electrical stimulation. In comparison to the potentiating effect of 5-methoxytryptamine (a reference 5-HT4 receptor agonist), the rank order of agonist potency was BIMU 8 = BIMU 1 greater than DAU 6236 = 5-methoxytryptamine. In whole ileal segments, DAU 6236, BIMU 1 and BIMU 8 increased markedly (maximum increase, 200%) the frequency of peristalsis within the range of 0.1 to 3 microM. Micromolar concentrations of ICS 205-930, which is a low affinity antagonist of 5-HT4 receptors, were required to antagonize the facilitatory effect on cholinergic transmission caused by benzimidazolone derivatives and 5-methoxytryptamine (pA2 values, 6.5 in average) and to reverse the increase in the frequency of peristalsis induced by DAU 6236, BIMU 1 and BIMU 8. By contrast, the potent and selective 5-HT3 receptor antagonist ondansetron (1 microM) was ineffective. Our findings indicate that benzimidazolone derivatives act as agonists in the guinea pig ileum causing enhancement of acetylcholine release and peristaltic activity. The neural receptor site involved in the action of benzimidazolone derivatives and which showed low affinity for ICS 205-930 is probably identical to the putative 5-HT4 receptor subtype agonized by indoleamines and substituted benzamide derivative prokinetic agents.
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PMID:Benzimidazolone derivatives: a new class of 5-hydroxytryptamine4 receptor agonists with prokinetic and acetylcholine releasing properties in the guinea pig ileum. 157 56


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