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)

We have used the polymerase chain reaction technique to selectively amplify a guanine nucleotide-binding protein-coupled receptor cDNA sequence from rat striatal mRNA that exhibits high homology to previously cloned serotonin receptors. Sequencing of a full length clone isolated from a rat striatal cDNA library revealed an open reading frame of 1311 base pairs, encoding a 437-residue protein with seven hydrophobic regions. Within these hydrophobic regions, this receptor was found to be 41-36% identical to the following serotonin [5-hydroxytryptamine (5-HT)] receptors: 5-HT2 > 5-HT1D > 5-HT1C > 5-HT1B > 5-HT1A > 5-HT1E. Northern blots revealed a approximately 4.2-kilobase transcript localized in various brain regions, with the following rank order of abundance: striatum >> olfactory tubercle > cerebral cortex > hippocampus. Expression of this clone in COS-7 cells resulted in the appearance of high affinity, saturable binding of (+)-[2-125I] iodolysergic acid diethylamide ([125I]LSD) with a Kd of 1.26 nM. Among endogenous biogenic amines, only 5-HT completely inhibited [125I]LSD binding (Ki = 150 nM). The inhibition of [125I]LSD binding by other serotonergic agonists and antagonists revealed a pharmacological profile that does not correlate with that of any previously described serotonin receptor subtype. In addition, this receptor exhibits high affinity for a number of tricyclic antipsychotic and antidepressant drugs, including clozapine, amoxipine, and amitriptyline. In HEK-293 cells stably transfected with this receptor, serotonin elicits a potent stimulation of adenylyl cyclase activity, which is blocked by antipsychotic and antidepressant drugs. The distinct structural and pharmacological properties of this receptor site indicate that it represents a completely novel subtype of serotonin receptor. Based on its affinity for tricyclic psychotropic drugs and its localization to limbic and cortical regions of the brain, it is likely that this receptor may play a role in several neuropsychiatric disorders that involve serotonergic systems.
Mol Pharmacol 1993 Mar
PMID:Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. 768 Jul 51

Glucocorticoids and serotonin (5-HT) modulate behaviour and hypothalamic-pituitary-adrenal (HPA) axis responses. The two systems interact prominently in the hippocampus, where these effects may occur. We have previously shown that hippocampal 5-HT2C receptor mRNA expression is increased by adrenalectomy or central 5-HT lesions. We have now determined expression of corticosteroid and 5-HT receptor subtype genes in the hippocampus across the diurnal cycle, when there are changes both in plasma corticosterone and hippocampal 5-HT levels, as well as the responses of these transcripts to acute and chronic stress, using in situ hybridisation histochemistry. Expression of both glucocorticoid (GR) and mineralocorticoid (MR) receptor mRNAs was significantly higher (131-153%) in the hippocampus at 08.00 h (corticosterone nadir) than at 20.00 h (corticosterone peak). 5-HT2C receptor mRNA expression also showed circadian variation (106-184% higher in CA1-CA3 in the morning). Hippocampal 5-HT1A and 5-HT2A receptor mRNA expression had no diurnal variation. Chronic (15 day) adjuvant arthritis stress, abolished the circadian corticosterone nadir, maintaining plasma corticosterone around diurnal peak values. Chronic arthritis stress suppressed hippocampal 5-HT2C receptor mRNA expression at 08.00 h to levels comparable to 20.00 h controls. By contrast to chronic stress, 6 h after acute laparotomy stress, plasma corticosterone was elevated above control (20.00 h) and 5-HT2C receptor mRNA expression was increased (CA2). Neither acute nor chronic stress altered MR, GR, 5-HT1A or 5-HT2A receptor mRNA expression in any hippocampal subfield. These results show that hippocampal expression of the 5-HT2C receptor gene, but not other subtypes, is sensitive to a variety of manipulations.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1995 Feb
PMID:Modulation of serotonin and corticosteroid receptor gene expression in the rat hippocampus with circadian rhythm and stress. 772 17

5-HT1a receptors in the hippocampus play a critical role in modulating limbic system output. The activity and level of 5-HT1a receptors are modulated by glucocorticoid levels. The present study was undertaken to test the hypothesis that glucocorticoids attenuate the transcriptional activity of the 5-HT1a receptor gene. Using in situ hybridization and RNase protection assays, we observed a substantial increase in 5-HT1a mRNA expression after adrenalectomy in the same hippocampal regions in which 5-HT1a binding sites are increased. This increase in 5-HT1a mRNA expression occurs as early as 1 h after adrenalectomy and precedes the increase in receptor binding sites. Further in situ hybridization analysis showed that 5-HT1a mRNA is increased within individual hippocampal cells after adrenalectomy. Administration of dexamethasone completely prevents the adrenalectomy-induced elevation in hippocampal 5-HT1a receptor mRNA. Nuclear run-on assays showed that the rate of transcription of 5-HT1a mRNA after adrenalectomy increased 70% above the rate from control preparations and could be reduced to basal levels by the administration of dexamethasone. Adrenalectomy did not cause an increase in functional coupling of 5-HT1a receptors to adenylyl cyclase or phospholipase C. These results suggest that transcription of hippocampal 5-HT1a receptor mRNA is under negative regulation by corticosteroid hormones.
Brain Res Mol Brain Res 1995 Mar
PMID:Transcriptional regulation of hippocampal 5-HT1a receptors by corticosteroid hormones. 776 98

The present study investigates the comparative repopulation kinetics of 5-hydroxytryptamine (5-HT)1A, 5-HT1B, and 5-HT2A receptors in rat cortex homogenates after irreversible receptor inactivation by N-ethoxycarbonyl-1,2-ethoxydihydroquinoline. Adult male rats were administered a single subcutaneous dose of vehicle (1:1 ethanol/water) or N-ethoxycarbonyl-1,2-ethoxydihydroquinoline (10 mg/kg), and the recovery of 5-HT receptor subtypes was measured at various times after injection (4-336 hr). Despite comparable control Bmax values for 5-HT1A (84 +/- 2 fmol/mg of protein) and 5-HT1B (94 +/- 4 fmol/mg) subtypes, marked differences were noted in their 1) receptor production rates (r = 0.349 versus 0.235 fmol/mg of protein/hr), 2) receptor degradation rate constants (k = 0.0056 versus 0.0033 hr-1), and 3) half-lives of receptor recovery (124.1 versus 212.5 hr). For 5-HT2A receptors, both r and k for agonist [(+/-)-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane]- or antagonist ([3H]ketanserin)-labeled sites were markedly greater than the respective values for the 5-HT1 subtypes. In addition, the significantly different Bmax values for agonist- versus antagonist-labeled 5-HT2A receptors (79 +/- 4 versus 206 +/- 10 fmol/mg) were reflected exclusively as a 2.6-fold difference in receptor production rates, because degradation rate constants (k) were identical. Moreover, the stoichiometry of agonist-labeled to antagonist-labeled 5-HT2A receptors was not altered at any time point during recovery. These data indicate that 1) comparable receptor steady state Bmax values for 5-HT receptor subtypes may be due to markedly different receptor kinetic parameters (r and k), 2) differences in r and k are greater between 5-HT receptor families (i.e., 5-HT1 versus 5-HT2) than among subtypes within a family (i.e., 5-HT1A versus 5-HT1B), and, 3) despite marked changes in 5-HT2A receptor density, the percentage of receptors in the agonist-labeled, high affinity state is maintained.
Mol Pharmacol 1994 Dec
PMID:Comparative recovery kinetics of 5-hydroxytryptamine 1A, 1B, and 2A receptor subtypes in rat cortex after receptor inactivation: evidence for differences in receptor production and degradation. 780 31

Due to the high level of expression of mRNA for the 5-hydroxytrytamine (5-ht7) receptor in the hypothalamus and the high affinity of 5-HT for this receptor, [3H]5-HT binding was performed in rat hypothalamus to determine whether 5-ht7 receptor binding sites are present in animal tissue. [3H]5-HT binding was performed in the presence of 100 nM pindolol, which is inactive at 5-ht7 receptors but prevents the binding of [3H]5-HT to 5-HT1A and 5-HT1B receptor binding sites. Under these conditions, [3H]5-HT bound to a binding site with an affinity of 1.94 nM. Displacement studies showed the pharmacology of the hypothalamic binding site to correlate well with the published pharmacology of the 5-ht7 receptor (r = 0.921). The treatment of rats with fluoxetine (5 mg/kg/day, orally) for 21 days caused a significant reduction in the number of hypothalamic 5-ht7 receptor binding sites. These data suggest that the 5-ht7 receptor binding site is expressed in rat hypothalamus and that this receptor binding site is down-regulated after a chronic increase in the synaptic level of 5-HT.
Mol Pharmacol 1995 Jan
PMID:Identification of 5-hydroxytryptamine7 receptor binding sites in rat hypothalamus: sensitivity to chronic antidepressant treatment. 783 38

Quantitative receptor autoradiography was used to examine the 5-hydroxytryptamine (5-HT, serotonin) binding sites labelled with serotonin-5-O-carboxymethyl-glycyl-[125I]tyrosinamide ([125I]GTI) in human and guinea-pig brain. Competition experiments using 5-carboxamidotryptamine (5-CT), 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93129) and sumatriptan revealed monophasic displacement curves in various brain regions, suggesting that a homogeneous population of 5-HT1D binding sites was labelled. Displacement of [3H]5-HT (in the presence of 100 nM 8-hydroxy-2(N-dipropylamino)tetralin (8-OH-DPAT) and 100 nM mesulergine) with unlabelled GTI resulted in monophasic competition curves in substantia nigra, globus pallidus and central gray. In contrast, biphasic displacement was observed in hippocampus, nucleus accumbens, claustrum, caudate-putamen and frontal cortex. The distribution of [125I]GTI sites was compared to that of [3H]5-HT binding sites (under so-called '5-HT1D conditions', i.e. in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine, in order to block 5-HT1A and 5-HT1C sites, respectively) in human and guinea-pig brain. Qualitative analysis revealed differences in the distributions of [125I]GTI and [3H]5-HT binding sites. Regions such as CA3 and CA4 of the hippocampus, claustrum and putamen showed [3H]5-HT binding (under '5-HT1D conditions') but no [125I]GTI binding sites, indicating that [3H]5-HT labels besides a GTI sensitive (5-HT1D) receptor population, a non-5-HT1A/1B/1C/1D [3H]5-HT binding site in human and guinea-pig brain. The distribution of these non-5-HT1A/1B/1C/1D [3H]5-HT binding sites was studied with [3H]5-HT under conditions where 5-HT1A, 5-HT1C and 5-HT1D [3H]5-HT binding sites were saturated by the presence of 100 nM 8-OH-DPAT, 100 nM mesulergine and 1 microM GTI. Significant densities of these non-5-HT1A/1B/1C/1D sites were observed in cortical areas, hippocampal structures, nucleus accumbens, amygdala, caudate-putamen and claustrum. It is concluded that [125I]GTI does not label the 5-HT1E binding site, since all competition curves obtained with this radioligand were monophasic. By contrast, [3H]5-HT labels non-5-HT1A/1B/1C/1D [3H]5-HT binding sites, but it remains to be established whether these sites represent a single receptor population.
Brain Res Mol Brain Res 1994 Jan
PMID:A comparative autoradiographic study of 5-HT1D binding sites in human and guinea-pig brain using different radioligands. 816 19

Two months after bilateral adrenalectomy, 5-HT1A receptor mRNA labelling was decreased in the granular cell layer of the dentate gyrus but not in the pyramidal cell layer of Ammon's horn. Two month adrenalectomized rats given dexamethasone (10 micrograms/ml saline) 24 or 72 h before perfusion showed a progressive recovery in 5-HT1A mRNA labelling in the dentate gyrus. 5-HT1A expression may underlie hippocampal neuronal plasticity after long-term adrenalectomy.
Brain Res Mol Brain Res 1993 Sep
PMID:Loss of 5-HT1A receptor mRNA in the dentate gyrus of the long-term adrenalectomized rats and rapid reversal by dexamethasone. 823 36

Previous studies [Meller et al. (1990) Mol. Pharmacol., 37:231-237] have shown that a large receptor reserve exists for the inhibition of serotonin synthesis in rat cortex and hippocampus by the 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), whereas little or no reserve exists for the lower efficacy agonists ipsapirone and BMY 7378. The current studies were undertaken to determine if the above drugs exhibit similar relative efficacies and receptor reserves in an electrophysiological model of 5-HT1A receptor activation, i.e., the inhibition of dorsal raphe cell firing. Intravenous dose-response curves were constructed in untreated control rats, or in rats which received an injection of the irreversible receptor inactivator N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 6 mg/kg, s.c.) 24 hours before recording. All three drugs fully inhibited dorsal raphe cell firing in control rats (ED50's: 1.5 micrograms/kg, 8-OH-DPAT; 30.0 micrograms/kg, ipsapirone; 17.5 micrograms/kg, BMY 7378). However, unlike effects on serotonin synthesis, EEDQ treatments caused no depression of the maximal inhibitory response for any of the agonists, although all dose-response curves were shifted to the right (ED50's: 10.1 micrograms/kg, 6.7-fold shift, 8-OH-DPAT; 139.9 micrograms/kg, 4.7-fold shift, ipsapirone; 53.8 micrograms/kg, 3.1-fold shift, BMY 7378). Although the order of agonist efficacies was similar for both inhibition of serotonin synthesis and dorsal raphe cell firing (8-OH-DPAT > ipsapirone > BMY 7378), a large (> 50%) receptor reserve was estimated for all three drugs in this electrophysiological system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT1A agonists. 824 53

A series of new derivatives of 3-(1,2,5,6-tetrahydropyridin-4-yl)indole (4-THPI) has been synthesized, and their dissociation constants at the 5-HT1A and 5-HT2 serotonin (5-HT) receptor subtypes have been determined. The new data were combined with similar binding data on a related set of THPI analogs reported previously (Taylor et al. Mol. Pharmacol. 1988, 34, 42-53) and used to develop 3-dimensional quantitative structure-activity relationships (3-D QSARs) for these compounds at the 5-HT1A and 5-HT2 receptor sites, by the method of comparative molecular field analysis (CoMFA). Since the previous study included several conventional QSARs obtained by Hansch analysis, and the new compounds in some cases fall within the congeneric series used in those analyses, we were able to make a direct comparison of the predictive capabilities of CoMFA and Hansch analysis using identical training and test data sets. The overall quality of actual predictions of activity by both methods appears to be about the same, as assessed by the root mean square (rms) residuals between actual and predicted pKi values. On the one hand, the compounds most poorly predicted by the Hansch analysis were 34, 35, and 37, while compounds 30-33 were relative poorly predicted by CoMFA. However, a clear advantage of CoMFA is the ability to include diversely substituted or noncongeneric analogs that must be omitted from conventional QSAR analysis. Using the entire data set of 45 THPI analogs reported here, pKi predictions for six additional compounds having 5-heteroarylindole substituents gave rms residuals of 0.46 and 0.36 for the 5-HT1A and 5-HT2 models, respectively; this is close to the experimental error of the binding data. The significance of the CoMFA field graphs in terms of molecular features required for activity and selectivity at these 5-HT receptor subtypes is discussed.
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PMID:Three-dimensional quantitative structure-activity relationships of 5-HT receptor binding data for tetrahydropyridinylindole derivatives: a comparison of the Hansch and CoMFA methods. 825 22

Agonists for GTP-binding protein (G protein)-coupled receptors are thought to bind with high affinity to the complex of receptor and G protein. Nonhydrolyzable GTP analogs have been shown to disrupt this complex and reduce the binding affinity for many agonists. Antagonists are thought to bind to the receptor whether or not it is coupled to the G protein, and therefore binding remains unchanged in the presence of GTP analogs. The binding of the serotonin 5-hydroxytryptamine (5-HT)2 receptor agonists serotonin (5-HT) and 4-bromo-2,5-dimethoxyphenylisopropylamine is not affected by the presence of GTP analogs when the cloned 5-HT2 receptor is expressed in the 293 human embryonic kidney cell line. The same receptor expressed in mouse NIH3T3 cells is partially sensitive to GTP analogs. Both cell lines have similar proportions of agonist and antagonist binding sites, and agonist stimulation of both cell lines leads to a robust increase in phosphoinositide hydrolysis. Differences in GTP metabolism in 293 cells is not likely to be the cause of the observed difference in inhibition of agonist binding, because the cloned 5-HT1A serotonin receptor expressed in these cells is sensitive to GTP analogs. The GTP-insensitive agonist binding is best explained by the existence of a G protein-receptor complex in 293 cells that is not sensitive to GTP analogs. Such a G protein-receptor complex may explain the fraction of agonist binding in the brain that is not sensitive to GTP analogs.
Mol Pharmacol 1993 Jun
PMID:High affinity agonist binding to cloned 5-hydroxytryptamine2 receptors is not sensitive to GTP analogs. 831 23


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