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)

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.
Mol Pharmacol 1990 Mar
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.
Mol Pharmacol 1990 May
PMID:Serotonin receptor-mediated activation of adenylate cyclase in the neuroblastoma NCB.20: a novel 5-hydroxytryptamine receptor. 233 46

Distinct membrane receptors that elicit similar cellular responses may share elements of signal transduction. In the present study, rat hippocampal adenosine (AD) and 5-hydroxytryptamine (5-HT) receptors were chosen to test this possibility using biochemical and electrophysiological techniques. Responses elicited by the AD receptor that mediates the inhibition of forskolin-stimulated adenylyl cyclase activity in rat hippocampal membranes and hyperpolarization of resting membrane potential (RMP) in rat hippocampal pyramidal cells were characterized and compared, in the same preparation, with those analogous responses elicited by the 5-HT1A receptor. A series of AD agonists including the selective AD A1 agonist (R)-phenylisopropyladenosine [(R)-PIA] inhibited forskolin-stimulated adenylyl cyclase activity in rat hippocampal membranes in a concentration-dependent manner. Cyclopentyltheophylline (CPT), a selective AD A1 antagonist, was a potent, competitive antagonist of this response with a dissociation constant (Kb) of 6 nM (Schild analysis). The rank order of agonist EC50 values and antagonist Kb values, as well as stereoselectivity, are consistent with the classification of this receptor as the AD A1 receptor. Spiperone, a potent 5-HT1A antagonist, competitively antagonized 5-HT-mediated inhibition of forskolin-stimulated adenylyl cyclase activity in rat hippocampal membranes with a Kb value of 14 nM. Intracellular recording techniques revealed that AD, (R)-PIA, 5-HT, and 5-carboxyamidotryptamine (5-CT) elicited concentration-dependent hyperpolarization of RMP within the same hippocampal pyramidal cell. The maximal hyperpolarization obtained for the AD or 5-HT analogs was the same for individual pyramidal cells. CPT and spiperone antagonized the hyperpolarization by (R)-PIA and 5-CT, respectively. Saturating concentrations of spiperone failed to antagonize (R)-PIA-mediated responses and CPT did not block responses elicited by 5-HT in either the biochemical or electrophysiological preparations. The combination of saturating concentrations of 5-HT and (R)-PIA evoked nonadditive biochemical responses relative to those observed with (R)-PIA alone. Similarly, electrophysiological experiments conducted under voltage-clamp conditions demonstrated that maximally effective concentrations of AD and 5-CT exhibited nonadditive behavior. Because the amount of outward current elicited when these agonists were coperfused was significantly less than the algebraic sum of the currents evoked individually by these agents, we infer that a population of AD A1 and 5-HT1A receptors activates a common pool of guanine nucleotide-binding proteins.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1989 Apr
PMID:Pertussis toxin-sensitive guanine nucleotide-binding protein(S) couple adenosine A1 and 5-hydroxytryptamine1A receptors to the same effector systems in rat hippocampus: biochemical and electrophysiological studies. 249 34

Serotonin (5-hydroxytryptamine, 5-HT) inhibited the formation of cAMP promoted by vasoactive intestinal polypeptide, plus forskolin, in mouse hippocampal and cortical neurons in primary culture. The rank order of potencies of classical 5-HT1 agonists in inhibiting cAMP formation in hippocampal neurons was 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) greater than 5-carboxamidotryptamine (5-CT) greater than d-lysergic acid diethylamide greater than 5-HT greater than 5-methoxy-N,N-dimethyltryptamine (5-MeO-N,N-DMT) greater than RU 24969 greater than ipsapirone greater than bufotenine greater than buspirone [half-maximal efficacy (EC50) = 7, 18, 30, 52, 90, 102, 100, 110, and 128 nM, respectively]. All the tryptamine derivatives substituted in position 5 of the indol were potent agonists [5-HT, 5-CT, 5-MeO-N,N-DMT, 5-methoxytryptamine, and bufotenine], whereas tryptamine, N-methyltryptamine, and N,N-dimethyltryptamine were poor agonists. The most potent antagonists tested were spiperone, (+/-)-pindolol, (+/-)-cyanopindolol, WB4101, and methiothepin, the affinity of spiperone for this receptor being 22 nM. In contrast, ketanserin, a specific 5-HT2 antagonist, and 5-HT3-selective drugs (ICS 205 930 and MDL 72222) were very weak in antagonizing the 5-HT-inhibited cAMP formation. The pharmacological profiles of 5-HT receptors mediating the inhibition of cAMP formation indicate that these receptors correspond to the 5-HT1A-binding site subtypes. Experiments with the Bordetella pertussis toxin indicate that the 5-HT1A receptor mediating inhibition of cAMP production involves a pertussis toxin-sensitive GTP-binding protein. In the absence of VIP, cAMP formation could be stimulated through a 5-HT receptor, but the specific 5-HT1A agonists, 8-OH-DPAT and RU 24969 did not stimulate cAMP production. These results suggest that in mouse embryonic hippocampal neurons, the 5-HT1A receptors, which are negatively coupled to adenylate cyclase, are distinct from the receptor positively coupled to this enzyme. The pharmacological characterization of the 5-HT receptor negatively coupled to adenylate cyclase in mouse embryonic cortical neurons indicates that it differs from the 5-HT1A receptor found in hippocampal neurons. Its main differences with the 5-HT1A receptor in hippocampal neurons are as follows: 1) 8-OH-DPAT was only a poor partial agonist in cortical neurons, whereas it was the best full agonist in hippocampal neurons; and 2) metergoline and methysergide as well as the anxiolytic drugs, ipsapirone and buspirone, which were potent agonists in hippocampal neurons, were competitive antagonists in cortical neurons.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1988 Feb
PMID:Pharmacology of 5-hydroxytryptamine-1A receptors which inhibit cAMP production in hippocampal and cortical neurons in primary culture. 282 13

A nonclassical 5-hydroxytryptamine (5-HT) receptor mediates the stimulation of adenylate cyclase activity in mouse embryo colliculi neurons in primary culture. The pharmacological profile characterized with agonists and antagonists suggests that this 5-HT receptor does not appear to correspond to a known 5-HT receptor. On this 5-HT receptor, 5-HT (EC50 = 109 +/- 17 nM) and 5-methoxytryptamine (5-MeOT) were equipotent agonists. The other tryptamine derivatives, 5-carboxamidotryptamine (5-CT) and 5-methoxy-N,N-dimethyltryptamine (5-MeOT-N,N-DMT), were full potent agonists, whereas tryptamine, bufotenine, and 2-CH3-5-HT were weak partial agonists. Two selective 5-HT1A agonists: 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and ipsapirone, could not stimulate adenylate cyclase. RU 24969, a tetrahydropyridoindole derivative that is a potent 5-HT1A and 5-HT1B agonist was also inactive, whereas RU 28253, another member of this series, could stimulate cAMP production. The action of antagonists acting on 5-HT1 or 5-HT2 receptors, such as methiothepin (5-HT1 and 5-HT2), metergoline (5-HT1 and 5-HT2), spiperone (5-HT1A and 5-HT2), (-)-pindolol (5-HT1B), mesulergine (5-HT1C), and ketanserin (5-HT2), were almost inactive in reversing the 5-HT stimulating effect. The selective 5-HT3 antagonist ICS 205 930 was a full competitive antagonist at this receptor. Nevertheless, MDL 72222, which is also a 5-HT3 antagonist, was very weak in antagonizing the 5-HT stimulatory effect. A receptor with similar characteristics has also been found in guinea pig hippocampal membranes. In these membranes, the second receptor of low affinity for 5-HT, termed RL, which is positively coupled to adenylate cyclase, was also antagonized by ICS 205 930. The relatively low affinity of this hippocampal receptor for 5-CT, its stimulation by RU 28253 but not by RU 24969, and its previously reported pharmacological characteristics support the contention that this 5-HT receptor and the 5-HT receptor of mouse embryo colliculi neurons in primary culture (both positively coupled to cAMP formation) present great homologies. Inasmuch as none of the classical specific 5-HT1 and 5-HT2 agonists or antagonists interact with these 5-HT receptors, it is unlikely that they belong to 5-HT1 or 5-HT2 receptor categories.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1988 Dec
PMID:A nonclassical 5-hydroxytryptamine receptor positively coupled with adenylate cyclase in the central nervous system. 284 52

In the presence of a 30 nM prazosin mask, [3H]-2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane ([3H]WB4101) can selectively label 5-HT1 serotonin receptors. Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for [3H] WB4101 binding in cerebral cortex. Furthermore, we have found a significant correlation (r = 0.96) between the affinities of a number of serotonergic and nonserotonergic compounds at [3H]WB4101-binding sites in the presence of 30 nM prazosin and [3H] lysergic acid diethylamide ([3H]LSD)-labeled 5-HT1 serotonin receptors in homogenates of rat cerebral cortex. Despite similar pharmacological profiles, distribution studies indicate that, in the presence of 5 mM MgSO4, the Bmax of [3H]WB4101 is significantly lower than the Bmax of [3H]LSD in various brain regions. WB4101 competition for [3H] LSD-labeled 5-HT1 receptors fits best to a computer-derived model assuming two binding sites, with the KH for WB4101 being similar to the KD of [3H]WB4101 binding derived from saturation experiments. This suggests that [3H]WB4101 labels only one of the subtypes of the 5-HT1 serotonin receptors labeled by [3H]LSD. Interestingly, the selective 5-HT1A serotonin receptor antagonist, spiperone, and the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetraline, exhibit high affinity and monophasic competition for [3H]WB4101 but compete for multiple [3H]LSD 5-HT1 binding sites. These data indicate that [3H]WB4101 selectively labels the 5-HT1A serotonin receptor, whereas [3H] LSD appears to label both the 5-HT1A and the 5-HT1B serotonin receptor subtypes. The divalent cations, Mn2+, Mg2+, and Ca2+ were found to markedly increase the affinity and Bmax of [3H]WB4101 binding in cerebral cortex. Conversely, the guanine nucleotides guanylylimidodiphosphate and GTP, but not the adenosine nucleotide ATP, markedly reduce the Bmax of [3H]WB4101 binding. These characteristics are typical of agonists interacting with receptors which modulate cellular function via a guanine nucleotide-regulatory subunit.
Mol Pharmacol 1985 Dec
PMID:[3H]WB4101 labels the 5-HT1A serotonin receptor subtype in rat brain. Guanine nucleotide and divalent cation sensitivity. 286 62

Two 5-hydroxytryptamine (5-HT) receptors mediate stimulation of adenylate cyclase activity in membranes of adult guinea pig hippocampus. The two receptors were characterized with agonists and antagonists and with the aid of computerized curve-fitting procedures. Each receptor mediates about 50% of the maximal response to 5-HT. 5-HT is about 10-fold more potent in eliciting response through one cyclase-linked receptor (RH) than the other (RL). The concentrations of 5-HT that elicit half-maximal response through RH and RL are 43 +/- 6 nM and 414 +/- 53 nM, respectively. 5-Methoxytryptamine (5-MeOT) and 5-HT are approximately equipotent at each receptor. The agonists tryptamine and bufotenine are less potent than 5-HT at both receptors, and each is about 50-fold selective for RH. The two receptors are best discriminated by the agonists 5-carboxamidotryptamine (5-CONH2-T) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), both of which are selective for RH. 5-CONH2-T is about 7-fold more potent than 5-HT at RH. The rank order of agonist potencies at RH (5-CONH2-T greater than 8-OH-DPAT = 5-HT = 5-MeOT greater than bufotenine greater than tryptamine) differs from that at RL (5-HT = 5-MeOT greater than bufotenine greater than tryptamine = 5-CONH2-T greater than 8-OH-DPAT). Spiperone acts as a simple competitive antagonist at RH, with a dissociation constant of 20 nM, but it is at least 100-fold less potent as an antagonist at RL. The relatively low affinities of the selective 5-HT antagonists ketanserin and MDL 72222 for RH and RL indicate that neither receptor may be classified as the 5-HT2 or as the 5-HT3 (i.e., peripheral neuronal) type. The characteristics of RH suggest that it is a functional correlate of the 5-HT1A-binding site in brain. RL appears not to correspond to a known 5-HT-binding site, but it may be homologous to receptors that mediate 5-HT-stimulated adenylate cyclase activity in other systems such as infant rat colliculi. RH and RL may also mediate stimulation of adenylate cyclase activity by 5-HT in hippocampal membranes of adult rat.
Mol Pharmacol 1987 Apr
PMID:Pharmacological characterization of two 5-hydroxytryptamine receptors coupled to adenylate cyclase in guinea pig hippocampal membranes. 295 74

The sulfhydryl reagents p-chloromercuribenzoate and N-ethylmaleimide (NEM) inactivate high affinity [3H]serotonin [( 3H]5-HT) binding to bovine and rat brain membranes in a concentration-dependent manner. In both species, 15-25% of total specific high affinity [3H]5-HT binding is relatively insensitive to NEM. This study examines the NEM sensitivity of the various high affinity [3H]5-HT binding subtypes, using selective ligands, tissues, and pharmacological masks to study each subtype. Reconstitution of NEM-inactivated binding by addition of GTP-binding proteins (G proteins, Gi and Go) is also described. Agonist binding to 5-HT1A, 5-HT1B, and 5-HT1D sites in rat brain and to 5-HT1A and 5-HT1D sites in bovine brain is sensitive to NEM. Binding of [3H]dihydroergotamine and [125I]iodocyanopindolol, both of which are weak partial agonists to 5-HT1B sites is relatively insensitive to NEM. Binding of [3H]5-HT to 5-HT1C sites in rat and bovine brain and choroid plexus is relatively insensitive to NEM. In the presence of spiperone to mask binding of 5-HT2 sites, binding of antagonist [( 3H]mesulergine) to 5-HT1C sites is also insensitive to NEM. Likewise, binding of the agonist [3H]4-bromo-2,5-dimethoxyphenylisopropylamine and of the antagonist [3H]ketanserin to 5-HT2 sites is not inhibited by NEM treatment of membranes. These findings suggest that agonist binding to 5-HT1A, 5-HT1B, and 5-HT1D sites is sensitive to NEM alkylation. Binding of neither agonist nor antagonist to 5-HT1C and 5-HT2 sites is sensitive to NEM. Inability of high concentrations of a variety of ligands to protect the sensitive binding sites against NEM inactivation indicates that the critical sulfhydryl group(s) are not located in the ligand binding domain of the NEM-sensitive binding sites. When membranes are treated with NEM, displacement of [125I]iodocyanopindolol by 5-HT is no longer sensitive to 5'-guanylyl imidodiphosphate (Gpp(NH)p). Gpp(NH)p sensitivity of agonist displacement of 5-HT1B binding to NEM-treated membranes is restored by addition of purified guanine nucleotide binding proteins (Gi plus Go). In addition, NEM-inactivated binding to 5-HT1A and 5-HT1D sites can be restored by addition of Gi plus Go. These data suggest that NEM exerts its effects on 5-HT1A, 5-HT1B, and 5-HT1D binding sites by inactivating the G protein(s) associated with the 5-HT receptor subtypes.
Mol Pharmacol 1988 Oct
PMID:Differential inactivation and G protein reconstitution of subtypes of [3H]5-hydroxytryptamine binding sites in brain. 313 89

The putative serotonin (5-HT) agonist RU 24969 [5-methoxy-3-1,2,3,6-tetrahydropyridin-4-yl)indole; 5-MeO-THPI] has been extensively used in the study and classification of 5-HT receptors. In order to study molecular determinants for recognition of THPIs at central 5-HT recognition sites, about 25 additional THPI derivatives were synthesized, incorporating, among others, 16 different indole-5-substituents and three different pyridine-N substituents in various combinations. Two saturated derivatives (piperidin-4-ylindoles) and two 2-methyl analogs were also included. Binding affinities at 5-HT1A, 5-HT2, and total 5-HT1 sites were obtained and the data were incorporated in quantitative structure-activity relationships (QSARs) using a combined linear free energy/molecular modeling approach. The QSAR analyses suggest distinct differences in the structural features that determine optimal potency at 5-HT1A sites versus those directing optimal potency for 5-HT2 sites. The parameter of the indole-5 substituent that almost exclusively determines potency for 5-HT1A sites is volume, the optimal size being about 24 cubic angstroms (calculated by fitting the activity versus volume data to a bilinear function). This is approximately the size of a carboxamide group. In contrast, at the 5-HT2 site both volume and hydrophobicity play major but opposing roles for the 5-substituent. A balance between the smallest possible volume and the greatest possible hydrophobicity is required for maximal 5-HT2 potency. Benzyl groups on the indole-1 or pyridyl-1 positions also favor potency at the 5-HT2 site (probably largely due to increased hydrophobic binding) while decreasing potency at the 5-HT1A site. A minor electronic contribution to the QSARs involving the charge on the indole 5-carbon is of opposite sign for 5-HT1A versus 5-HT2 sites and thus may also be useful for selective drug design. The data are consistent with the possibility that the indole and pyridyl rings are in a coplanar configuration when binding at both 5-HT1A and 5-HT2 sites, because the indole-2-methyl substituent, which provides a large energy barrier to the coplanar configuration, greatly reduces the potency of THPIs at both binding sites. Similarities in analog selectivity patterns suggest that the indolic portion of these compounds binds similarly to that of other indole derivatives such as tryptamines; thus, it is possible that optimally selective substituents predicted by these QSARs may be extrapolated to tryptamines and other indoles.
Mol Pharmacol 1988 Jul
PMID:Molecular determinants for recognition of RU 24969 analogs at central 5-hydroxytryptamine recognition sites: use of a bilinear function and substituent volumes to describe steric fit. 339 40

Groups of rats were treated with buspirone (1 mg/kg/day) for 21 days using osmotic minipumps implanted subcutaneously. After buspirone treatment, the 5-HT1A receptor mRNA levels were significantly decreased in the CA1 and CA2 of the hippocampus, but were markedly increased in the dentate gyrus (DG), CA3 and CA4. The level of the 5-HT1A receptor binding sites was not significantly changed in these subhippocampal areas. Buspirone treatment markedly increased 5-HT2A receptor mRNA levels in the DG, CA2, CA3 and CA4. This was accompanied by a significant increase in the level of 5-HT2A receptor binding sites in all subhippocampal regions. These results demonstrate that chronic buspirone treatment differentially regulates 5-HT1A and 5-HT2A receptor mRNA as well as their expressed binding sites in various regions of the hippocampus.
Brain Res Mol Brain Res 1995 Sep
PMID:Chronic buspirone treatment differentially regulates 5-HT1A and 5-HT2A receptor mRNA and binding sites in various regions of the rat hippocampus. 750 Aug 48


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