Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study deals with the characterization of 5-hydroxytryptamine (5-HT, serotonin) receptors positively linked to adenylyl cyclase in membranes from pig brain caudate. 5-HT and related agonists induced a concentration-dependent stimulation of adenylyl cyclase activity in pig caudate membranes, with the following rank order of potency (mean pEC50 values): 5-HT (7.1) > or = 5-methoxytryptamine (6.9) > 5-carboxamidotryptamine (5.6) > sumatriptan (< 5). Maximal stimulation by 5-HT averaged 35 pmol cyclic AMP/min/mg protein over a basal activity of 159 pmol cyclic AMP/min/mg protein. 5-Methoxytryptamine and 5-carboxamidotryptamine had similar efficacies to that of 5-HT, whereas sumatriptan was about half efficacious. Other compounds known as agonists at some 5-HT receptors were weakly potent (mean pEC50 values < 5). They include the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), the 5-HT4 receptor agonist, renzapride and the 5-HT2 receptor agonist, (1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane) (DOI). In antagonist studies, methiothepin (0.1 and 1 mumol/l) shifted the 5-HT curve to the right with no depression of the Emax, yielding pKB values of 7.4-8.0. Clozapine (1 mumol/l) also produced surmountable antagonism of 5-HT-induced effects (pKB 6.9). Ketanserin (10 mumol/l) weakly antagonized 5-HT (pKB 5.0). The 5-HT4 receptor antagonists, tropisetron (ICS 205-930) and SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester), each at 1 mumol/l, did not significantly alter the concentration-response curve of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes. 784 73

1. 5-Hydroxytryptamine (5-HT) has been shown to induce contraction of tracheal smooth muscle. However, the mechanisms of action of 5-HT are not known. We therefore investigated the effects of 5-HT on phospholipase C (PLC)-mediated phosphoinositide (PI) hydrolysis and its regulation in canine cultured tracheal smooth muscle cells (TSMCs) labelled with [3H]-inositol. 5-HT-induced inositol phosphates (IPs) accumulation was time- and dose-dependent with a half-maximal response (EC50) and a maximal response at 0.38 +/- 0.05 and 10 microM, respectively. 2. Ketanserin and mianserin (10 and 100 nM), 5-HT2 receptor antagonists, were equipotent in blocking the 5-HT-induced IPs accumulation with pKB values of 8.46 and 8.21, respectively. In contrast, the dose-response curves of 5-HT-induced IPs accumulation were not shifted until the concentrations of NAN-190 and metoclopramide (5-HT1A and 5-HT3 receptor antagonists, respectively) were increased up to 10 microM. 3. Pretreatment of TSMCs with pertussis toxin or cholera toxin did not inhibit the 5-HT-induced IPs accumulation, but partially inhibited the AlF(4-)-induced IPs response. 4. Stimulation of IPs accumulation by 5-HT required the presence of external Ca2+ and was blocked by EGTA. The addition of Ca2+ (3-620 nM) to digitonin-permeabilized TSMCs directly stimulated IPs accumulation. A further Ca(2+)-dependent increase in IPs accumulation was obtained by inclusion of either guanosine 5'-O-(3-thiotriphoshate) (GTP gamma S) or 5-HT. The combination of GTP gamma S and 5-HT elicited an additive effect on IPs accumulation. 5. Treatment with phorbol 12-myristate 13-acetate (PMA, 1 microM, 30 min) abolished the 5-HT-induced IPs accumulation. The concentrations of PMA that gave a half-maximal and maximal inhibition of 5-HT-induced IPs accumulation were 2.2 +/- 0.4 nM and 1 microM, n = 3, respectively. The protein kinase C (PKC) activator, 4 alpha-phorbol 12,13-didecanoate, at 1 microM, did not influence this response. The inhibitory effect of PMA was reversed by staurosporine, a PKC inhibitor, suggesting that the inhibitory effect of PMA is mediated through the activation of PKC. 6. The site of this inhibition was further investigated by examining the effect of PMA on AlF(4-)-induced IPs accumulation in canine TSMCs. AlF(4-)-stimulated IPs accumulation was inhibited by PMA treatment, suggesting that the effect of PMA is distal to the 5-HT receptor. 7. Acetylcholine-induced IPs accumulation was completely inhibited by atropine, but not affected by ketanserin or mianserin, suggesting that 5-HT-induced IPs accumulation is not due to release of acetylcholine.8. These results demonstrate that 5-HT directly stimulates PLC-mediated PI hydrolysis via a pertussis toxin- and cholera toxin-insensitive GTP binding protein in canine TSMCs and that this coupling process is negatively regulated by PKC. 5-HT2 receptors may be predominantly mediating IPs accumulation and presumably IP-induced Ca2+ release may function as the transducing mechanism for 5-HT stimulated contraction of tracheal smooth muscle.
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PMID:5-Hydroxytryptamine receptor-mediated phosphoinositide hydrolysis in canine cultured tracheal smooth muscle cells. 801 56

Repeated treatment with fluoxetine and citalopram, which are potent 5-HT reuptake inhibitors, resulted in different regulation of 5-HT1A and 5-HT2 receptors in the rat brain. Their effects were compared with those of other antidepressants: imipramine, mianserin and levoprotiline. The density of 5-HT1A receptors, labelled with [3H]8-OH-DPAT, in the rat hippocampus was enhanced after citalopram, imipramine, mianserin and levoprotiline, but not altered after fluoxetine administration. [3H]Ketanserin binding sites, which label 5-HT2 receptors, were increased after fluoxetine and levoprotiline, but decreased after citalopram, imipramine and mianserin in the rat cerebral cortex. Acute administration of fluoxetine, but not citalopram, resulted in a decreased density of 5-HT1A receptors. 5-HT2 receptors were not changed by acute administration of either fluoxetine or citalopram. The obtained results indicate that besides 5-HT reuptake inhibiting properties of both compounds, there may exist an additional mechanism(s) of their action, which leads to different regulation of 5-HT1A and 5-HT2 receptors.
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PMID:Effects of repeated treatment with fluoxetine and citalopram, 5-HT uptake inhibitors, on 5-HT1A and 5-HT2 receptors in the rat brain. 814 68

Intracellular recordings were made from neurons of the nucleus prepositus hypoglossi in slices of guinea pig medulla. 5-HT (serotonin) caused a hyperpolarization followed by a late depolarization. The hyperpolarization was mediated by 5-HT1A receptor activation and could be selectively blocked by pindobind-5HT1A (PBD). 5-HT then caused a depolarization only. A selective 5-HT2 agonist, (+)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), also caused a depolarization. Ketanserin and spiperone, 5-HT2 antagonists, blocked the depolarization due to both 5-HT and DOI. Focal electrical stimulation caused an IPSP mediated by 5-HT acting upon 5-HT1A receptors and a slow EPSP (s-EPSP). PBD blocked the IPSP, leaving an isolated s-EPSP. Both spiperone and ketanserin antagonized the s-EPSP, while DOI occluded it. The s-EPSP was from 2 to 10 mV in amplitude and 35-50 sec in duration, and showed voltage dependence consistent with a decrease in potassium conductance. Both the IPSP and the s-EPSP were presynaptically inhibited by the 5-HT1D agonist sumatriptan. These data indicate that the s-EPSP is mediated by 5-HT acting upon 5-HT2 receptors. This represents strong support for the role of 5-HT as an excitatory neurotransmitter in the CNS. Further, it demonstrates that synaptic release of 5-HT can mediate opposing effects on the membrane potential of a single cell.
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PMID:A slow excitatory postsynaptic potential mediated by 5-HT2 receptors in nucleus prepositus hypoglossi. 815 79

Pretreatment with the 5-HT2 antagonist ketanserin and the 5-HT1A/2 antagonist spiperone did not reduce nicotine-induced hypomotility in mice, nor did MDL 7222, a selective 5-HT3 antagonist. In addition, 8-OH-DPAT and buspirone, 5-HT1A agonists, had no significant effects on nicotine-induced hypomotility. However, 8-OH-DPAT and buspirone did reduce the antinociceptive effects of nicotine in a dose-dependent manner. 8-OH-DPAT blockade of this nicotine effect was reversed by spiperone, a 5-HT1A/2 antagonist. Nicotine's ED50 was increased from 1.00 mg/kg (0.90-1.68) to 2.00 mg/kg (1.6-2.55) and 2.66 (1.7-3.51) by buspirone and 8-OH-DPAT, respectively. Ketanserin, spiperone and MDL 7222 had no significant effect on nicotine-induced antinociception. The present data suggest an important role of 5-HT1A receptors in the modulation of antinociceptive actions of nicotine.
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PMID:Involvement of the serotonergic system in the hypoactive and antinociceptive effects of nicotine in mice. 827 40

The presence of serotonin (5-HT) in the chicken gastrointestinal tract has been previously reported, but its motor effects have been poorly described. The aims of this work were: A) to define the effects of 5-HT on chicken longitudinal ileum; B) to explore the mechanisms by which such effects occur and C) to identify the subtype(s) of 5-HT-ergic receptors implicated. The motor responses to 5-HT were assayed in vitro using ileal strips taken from male White Leghorn chickens 7-9 week old. 5-HT elicited ileal contraction (EC50 9.6 x 10(-8) M), which was markedly decreased in the presence of tetrodotoxin (TTX). Repeated exposure of the tissue to supramaximal concentrations of 5-HT did not however lead to desensitization. Atropine (10(-6) M), ketanserin (10(-5) M), methysergide (10(-5) M) and methiothepine (10(-6) M) attenuated the response to 5-HT. Ketanserin was an effective inhibitor of the residual response to 5-HT obtained even in the presence of TTX. Several serotonergic agonists were assayed to further analyse the type of receptors involved in the response to 5-HT. 5-methoxytryptamine (5-MOT), a mixed 5-HT1, 5-HT2 and 5-HT4 agonist, reproduced all the effects of 5-HT. 8-OH-DPAT, a selective 5-HT1A agonist, trifluoromethylphenylpiperazine, a mixed 5-HT1B/C agonist, and m-chlorophenylbiguanide, a 5-HT3 agonist, did not induce any consistent contractile effects. Sumatriptan, a 5-HT1D agonist, exerted a slight agonistic effect which was blocked by methiothepine and decreased by TTX but not by atropine. Cisapride, a 5-HT4 partial agonist in mammals, decreased the effects of both 5-HT and 5-MOT. These results indicate that chicken ileum contains 5-HT1 receptors similar to the 5-HT1D mammalian subtype but not the 5-HT1A, 5-HT1B, 5-HT1C or 5-HT3 subtypes. 5-HT2 receptors are also present and would appear to be located on smooth muscle.
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PMID:Receptors implicated in the actions of serotonin on chicken ileum longitudinal smooth muscle. 846 35

Serotonin (5-hydroxytryptamine; 5-HT) caused a transient increase in intracellular Ca2+ in C6BU-1 glioma cells in a concentration-dependent manner; half maximally at 73 nM. The 5-HT2 agonist 1-(4-iodo-2,5-dimethoxyphenyl)-2- aminopropane also increased the levels of intracellular Ca2+, whereas the 5-HT1C agonist 1-(3-chlorophenyl)piperazine and 5-HT1A agonist 8-hydroxy-2- (di-n-propylamino)tetralin were completely ineffective. Ketanserin and spiperone blocked the response to 5-HT at a nanomolar concentration, but the 5-HT3 antagonist MDL 72222 had no effect on it. Thus 5-HT2 receptors are responsible for activating Ca2+ mobilization in C6 glioma cells. Treatment of C6 glioma cells with dexamethasone potentiated the ability of 5-HT to cause intracellular Ca2+ mobilization in both a dose- and time-dependent manner. The dose-response curve for 5-HT was shifted 9-fold to the left compared to controls, and the Vmax value was also significantly enhanced. This enhanced Ca2+ mobilization was completely inhibited by ketanserin dose-dependently. In addition, the treatment with dexamethasone enhanced fluoride-activated Ca2+ mobilization, suggesting that the enhanced GTP binding protein function is one of the mechanisms responsible for the enhancement of the 5-HT response induced by dexamethasone treatment. This enhancement of agonist activity was mediated by the type II glucocorticoid receptor (GR) since RU 38486, an inhibitor of the type II GR, antagonized the dexamethasone-induced enhancement.
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PMID:Dexamethasone potentiates serotonin-2 receptor-mediated intracellular Ca2+ mobilization in C6 glioma cells. 851 Aug 6

In segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, we determined the effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on tritium overflow evoked by transmural electrical stimulation (2 Hz). Tritium overflow was inhibited by 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate (RU 24969) and sumatriptan. Yohimbine and oxymetazoline (in the presence of idazoxan) also inhibited tritium overflow. The inhibitory potency of the drugs was significantly correlated with their affinity for 5-HTID receptors in human brain and for cloned human 5-HT1D alpha and 5-HT1D beta receptors, but not with their affinity for 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT5B and 5-HT7 receptors. The potency order 5-CT > 5-HT > 5-MeOT is opposite to the order of affinities reported for 5-HT6 binding sites. The preferential 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (up to 0.3 microM) and the selective 5-HT4 receptor agonist cisapride (up to 1 microM) failed to inhibit tritium overflow. L-694,247, a potent 5-HT1D beta receptor agonist, did not inhibit tritium overflow, but counteracted the inhibitory effect of 5-HT. Ketanserin at a concentration which should block 5-HT1D alpha but not 5-HT1D beta receptors and methiothepin at a concentration which may be assumed to block both 5-HT1D alpha and 5-HT1D beta receptors antagonized the inhibitory effect of 5-HT. Propranolol and ondansetron did not modify the 5-HT-induced inhibition of release. In conclusion, noradrenaline release in human right atrial appendages is inhibited via 5-HT receptors which are located on the noradrenergic axon terminals. These inhibitory presynaptic 5-HT receptors belong to the 5-HT1D subfamily. The ability of ketanserin to antagonize the inhibitory effect induced by activation of these receptors suggests that they can be subclassified as 5-HT1D alpha.
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PMID:Inhibition of noradrenaline release via presynaptic 5-HT1D alpha receptors in human atrium. 869 81

The functional profiles of brain 5-HT1A and 5-HT2A/C receptors were assessed by quantitating changes in the immediate early genes -c-fos, ngf1c and tis1, following receptor activation with either 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) or DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane). Stimulation of either class of 5-HT receptor elicited an induction of all three immediate early genes to varying extents in cortex, hippocampus and cerebellum, but not in striatum. The responses to 8-OH-DPAT peaked earlier than those to DOI. WAY 100135 (N-tertiobutyl-3-[4-(2-methoxyphenyl)-piperazinyl]-2-phenylpropana mide), the putative 5-HT1A receptor antagonist blocked the 8-OH-DPAT effect but not the responses to DOI. WAY 100135 by itself also elicited a relatively smaller genomic response. Ketanserin completely abolished the DOI-induced genomic responses. The results support the earlier findings that 5-HT1A receptor sites are abundant in frontal cortex and hippocampus. In addition, the robust genomic responses to 8-OH-DPAT as well as Northern hybridization with a cDNA probe for 5-HT1A mRNA in the cerebellum clearly implicate the functional expression of 5-HT1A receptors in this brain region. The responses to the 5-HT2 receptor agonist, DOI support a greater abundance of these receptors in the cortex, and relatively lower levels in hippocampus and cerebellum. The results suggest a differential induction pattern among the three immediate-early genes depending on the brain region and the 5-HT receptor subtype involved.
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PMID:Genomic responses to 5-HT1A or 5-HT2A/2C receptor activation is differentially regulated in four regions of rat brain. 883 23

Repeated peripheral administration of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) induced significant changes in the binding activities of serotonergic receptors in the rat brain. The increase in the hippocampus and the decrease in the visual cortex of [3H]8-hydroxy-N,N-dipropyl-2-aminotetralin ([3H]8-OH-DPAT) binding (5-HT1A binding site) were found to be significant following R-THBP administration (20 mg/kg, twice a day for 1 week). [3H]Ketanserin binding (5-HT2 binding site) was increased in the striatum and hippocampus, whereas it was decreased in the cerebellum and visual cortex. Scatchard plot analysis showed ca. 20% reduction in the Bmax of [3H]8-OH-DPAT and [3H]ketanserin binding in the visual cortex, and KD values for [3H]8-OH-DPAT and [3H]ketanserin bindings in the hippocampus were significantly reduced 51% and 66%, respectively. These differential changes in 5-HT binding might be involved in the central action of R-THBP.
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PMID:Repeated peripheral administration of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin alters the binding activities of 5-HT1A and 5-HT2 receptors in rat brain. 888 12


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