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)

To determine whether a cloned receptor coupled to pertussis toxin (PTx)-sensitive G-proteins can induce cell proliferation and oncogenic transformation, as observed for receptors that elicit PTx-insensitive enhancement of phosphatidyl inositol (PI)-specific phospholipase-C (PLC) activity, nontransformed murine BALB/c-3T3 cells were transfected with the rat serotonin-1A (5-HT1A) receptor. The 5-HT1A receptor is coupled to PTx-sensitive G-proteins to induce a cell-specific activation of PLC. While 1 microM 5-HT induced no change in PI turnover or cytosolic free calcium levels ([Ca2+]i) in receptor-negative nontransfected 3T3 cells, 5-HT induced a 2-fold increase in inositol trisphosphate accumulation and a 2.5-fold increase in [Ca2+]i in the 3T3-ZD8 clone, which expressed 0.6 +/- 0.2 pmol/mg protein of specific 5-HT1A binding sites. The stimulatory actions of 5-HT on PI turnover and [Ca2+]i in 3T3ZD8 cells displayed the pharmacology of the 5-HT1A receptor and were abolished by pretreatment with PTx. Thus, BALB/c-3T3 fibroblast cells express the PLC-linked pathway of the 5-HT1A receptor. Overnight treatment with 5-HT (1 microM) enhanced incorporation of [3H]thymidine into DNA extracted from serum-starved 3T3ZD-8 cells, an action that was also blocked by pretreatment with pertussis toxin. Long term (1-2 weeks) exposure to 5-HT in the medium led to phenotypic transformation of the cells, including the formation of foci with 1 microM 5-HT. These actions of 5-HT were not observed in untransformed 3T3 cells. We conclude that the PTx-sensitive PLC-linked pathway of the 5-HT1A receptor expressed in nontransformed BALB/c-3T3 cells, in concert with other serum-derived factors, predisposes the cells to enhanced proliferation and transformation.
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PMID:Conditional transformation mediated via a pertussis toxin-sensitive receptor signalling pathway. 160 83

We report the cloning and expression of a novel 5-HT receptor gene from human genomic DNA. This clone, HGCR1, contains an apparently intronless open reading frame of 390 amino acids with the seven hydrophobic regions, typical of G-protein coupled receptors. The deduced amino acid sequence of HGCR1 is 39%, 55% and 87% identical to that for the human 5-HT1A, the human 5-HT1D and the rat 5-HT1B receptor, respectively. [3H]5-HT binding to transfected COS-7 cell membranes yields a pharmacological profile similar to that of 5-HT1B receptor. Thus these findings indicate the presence of 5-HT1B-type receptor in the human.
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PMID:Cloning and expression of the human 5-HT1B-type receptor gene. 161 Mar 47

Buspirone (BUSP) is a serotonergic (5-HT) agonist with activity at the 5-HT1A receptor. The BUSP induced prolactin (PRL) response was examined in 10 patients with a DSM IIIR diagnosis of obsessive-compulsive disorder (OCD). The results were compared with PRL responses to BUSP found in 10 age and sex matched healthy controls. The results suggest that the 5-HT1A receptor dysfunction may not be involved in the pathophysiology of OCD. The authors review the literature and consider the hypothesis that in OCD a complex interaction of other 5-HT receptor sub-types may be occurring, possibly with dysfunction primarily of the 5-HT2 receptors.
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PMID:Buspirone induced prolactin responses in obsessive-compulsive disorder (OCD): is OCD a 5-HT2 receptor disorder? 162 56

The regional distribution and pharmacological properties of [3H]tandospirone binding sites in the rat brain were investigated using quantitative autoradiography. [3H]Tandospirone binding was notably high in the dentate gyrus and CA1 area of the hippocampus, lateral septum, entorhinal cortex, interpeduncular nucleus and dorsal raphe nucleus. The distribution profiles of [3H]tandospirone binding sites significantly correlated with that of serotonin (5-HT)1A receptors identified using [3H]8-OH-DPAT. In competitive binding studies, [3H]tandospirone binding was inhibited by 5-HT, 8-OH-DPAT, pindolol, buspirone and N-(a,a,a-trifluoro-m-tolyl)-piperazine. The potencies of these ligands correlated with their affinities for 5-HT1A receptors. In addition, there was no significant difference in the dissociation constant of [3H]tandospirone binding between the dentate gyrus, CA1 area, dorsal raphe nucleus, lateral septum and entorhinal cortex (about 10 nM) suggesting that [3H]tandospirone binds to 5-HT1A receptors with same affinities in these brain structures. The distribution pattern of binding sites for [3H]tandospirone was also compared with that of benzodiazepine receptors identified using [3H]fludiazepam to find common effector sites for different types of anxiolytics. Some similarities were observed. It is evident in the hippocampal formation that an overlap of intense binding occurred. 5-HT1A receptors in the hippocampus may participate in the anxiolytic effects of tandospirone.
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PMID:Autoradiographic localization and pharmacological characterization of [3H]tandospirone binding sites in the rat brain. 164 88

The affinity of buspirone and its main metabolite 1-(2-pyrimidinyl)piperazine (PmP) for serotonin1 (5-HT1) and benzodiazepine receptors was first evaluated by computerized receptor autoradiography. The results confirmed that buspirone is a selective 5-HT1A ligand, since it inhibited the binding of [3H]5-HT with lower IC50 values (about 100 nM) in regions of the brain of the rat where this receptor subtype is predominant (such as hippocampal areas). Larger IC50 values than 3 microM were found in areas of the brain richer in 5-HT1 receptors, other than the 5-HT1A subtype (e.g. striatum, substantia nigra and the ventricles). The PmP was not selective, inhibiting the binding of [3H]5-HT with similar affinity (about 4-10 microM) in all the regions of the brain examined. Neither buspirone nor PmP, up to 100 microM, were active on benzodiazepine receptors. The autoradiographic technique was therefore used to evaluate the effects of acute (10 mg/kg, p.o., 1 hr before killing) and chronic (10 mg/kg, i.p., twice a day for 21 days, 24 hr washout) treatment with buspirone in male rats. Acute treatment reduced the binding of [3H]5-HT in all the regions of the brain studied, including those with low levels of 5-HT1A receptors, indicating the occupancy of 5-HT1 receptors by either buspirone or its metabolite. The binding of [3H]flunitrazepam was decreased (16%) only in the substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of acute and chronic administration of buspirone on serotonin and benzodiazepine receptor subtypes in the rat brain: an autoradiographic study. 164 18

1-(2-Methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190; 1a) is a putative postsynaptic 5-HT1A serotonin antagonist. This high affinity ligand (Ki = 0.6 nM), although selective for 5-HT1A versus other 5-HT receptors, binds with nearly equal affinity at alpha 1-adrenergic receptors (Ki = 0.8 nm). Structure-affinity relationship studies were conducted in order to achieve an improved selectivity. Replacement of the phthalimide moiety by substituted benzamides led to retention of 5-HT1A affinity but to no improvement in selectivity, whereas replacement by alkyl amides proved beneficial, leading to an improvement in affinity and selectivity. Branching alpha to the amide carbonyl group and increased bulkiness of the alkyl moiety further improved 5-HT1A affinity and selectivity. 4-[4-(1-Adamantanecarboxamido)butyl]-1- (2-methoxyphenyl)piperazine (2j) was found to bind at 5-HT1A sites with high affinity (Ki = 0.4 nM) and with a 160-fold selectivity over alpha 1-adrenergic sites. Preliminary studies show that this agent retains antagonist activity as determined in a 5-HT1A-coupled adenylyl cyclase assay. Further functional studies are warranted to fully characterize this agent.
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PMID:Analogues of the 5-HT1A serotonin antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine with reduced alpha 1-adrenergic affinity. 165 26

We describe the nucleic acid sequence encoding a human 5-hydroxytryptamine1D (5-HT1D) serotonin receptor and some of the functional characteristics of the gene product. The receptor gene was isolated by hybridization to a probe based on a canine thyroid cDNA (called RDC4) previously isolated by others and believed to encode a heretofore undetermined member of the guanine nucleotide-binding protein (G protein)-linked receptor family. The human clone we isolated, called MA6A, contains an apparently intronless open reading frame encoding a 377-amino acid polypeptide with the seven hydrophobic domains characteristic of G protein-linked receptors. The MA6A deduced amino acid sequence is 88% identical to that for RDC4 and 43% identical to that for the human 5-HT1A receptor. Expression of the human gene product in transfected cell lines results in the appearance of saturable high affinity 5-HT1D-type [3H]5-HT binding. The expressed receptor exhibits features indicative of coupling to Gi proteins, i.e., robust inhibition of forskolin-stimulated cAMP accumulation and formation of a pertussis toxin-sensitive high agonist affinity binding state. These findings may help clarify several ambiguities in the classification and action of serotonin receptor subtypes.
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PMID:Primary structure and functional characterization of a human 5-HT1D-type serotonin receptor. 165 50

We investigated the hypothesis that cocaine-induced elevations of plasma adrenocorticotropin hormone (ACTH) and corticosterone are mediated by brain serotonin (5-HT) neurons. Adult male rats were pretreated with the 5-HT depleting agent p-chlorophenylalanine, the 5-HT neurotoxin 5,7-dihydroxytryptamine, the partial 5-HT1A agonist 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-8- azaspirol[4,5]-decane-7,9-dione (BMY 7378) or the 5-HT1C/2 antagonist ritanserin. The effects of cocaine (2-15 mg/kg, i.p.) on plasma ACTH and corticosterone were then examined. Cocaine dose-dependently increased ACTH and corticosterone concentration. This increase was prevented by 5-HT depletion with PCPA and by destruction of 5-HT neurons with i.c.v. injections of 5,7-dihydroxytryptamine. The cocaine-induced elevation of ACTH and corticosterone was not significantly modified by administration of the partial 5-HT1A agonist BMY 7378, suggesting that 5-HT1A receptors probably do not mediate ACTH and corticosterone secretion. However, pretreatment with the 5-HT2/5-HT1C antagonist ritanserin virtually eliminated the cocaine-induced elevation of corticosterone. To determine whether these effects of cocaine are centrally mediated, conscious rats received cocaine injections into the cerebral ventricle through chronically implanted cannulas. Plasma ACTH concentrations were dose-dependently increased, whereas low doses (50 micrograms/kg, i.c.v.) produced a maximal increase in corticosterone concentration. These data indicate that the cocaine-induced stimulation of ACTH and corticosterone secretion is mediated by 5-HT neurons in brain, and furthermore, that 5-HT2 or 5-HT1C receptors are responsible for this effect.
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PMID:Cocaine-induced elevation of plasma adrenocorticotropin hormone and corticosterone is mediated by serotonergic neurons. 165

The effect of lithium administration (800 mg daily for 7 days) on the neuroendocrine and temperature responses to the 5-HT1A receptor agonist, gepirone, was studied in eight healthy male volunteers. Gepirone (20 mg orally) significantly increased plasma levels of prolactin, growth hormone, corticotropin and cortisol, and lowered oral temperature. None of these responses was significantly altered by lithium treatment. The results suggest that the ability of short-term lithium treatment to increase 5-HT-mediated neuroendocrine responses in humans is unlikely to be related to changes in the sensitivity of pre- or post-synaptic 5-HT1A receptors.
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PMID:Lithium and 5-HT1A receptor sensitivity: a neuroendocrine study in healthy volunteers. 166 54

The aim of the present study was to assess the effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and flesinoxan in ring preparations of human basilar artery. 5-Hydroxytryptamine-(5-HT), 8-OH-DPAT and flesinoxan induced concentration-dependent contractions of human basilar artery, the rank order of agonist potency being 5-HT greater than 8-OH-DPAT approximately flesinoxan. The rank order of maximum response, relative to 5-HT was 5-HT (100%) much greater than 8-OH-DPAT (40.4 +/- 4.4%) much greater than flesinoxan (7.0 +/- 2.3%). The contractile effects of 8-OH-DPAT were blocked by phentolamine (10 microM) but not by labetalol (10 microM). Spiperone (1 microM) had no significant effect on either 5-HT or 8-OH-DPAT-induced contraction, however methiothepin (100 nM) produced inhibition of both 5-HT- and 8-OH-DPAT-induced contraction of human basilar artery. In addition, flesinoxan (100 microM) produced blockade of 5-HT-, 8-OH-DPAT- and sumatriptan (a 5-HT1-like receptor agonist)-induced contraction of human basilar artery, although full concentration-effect curves were not obtained. In some preparations 8-OH-DPAT produced a concentration-dependent relaxation of tone. This effect was particularly apparent in the presence of phentolamine. We conclude from the relative rank order of antagonist potency that 8-OH-DPAT and 5-HT produce contraction of the human basilar artery by activation of the same receptor, a 5-HT1-like receptor distinct from the 5-HT1A receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contractile effects of 8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan in human isolated basilar artery. 166 3


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