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)

5-Hydroxytryptamine (serotonin or 5-HT) stimulated the incorporation of 32Pi into phosphatidylinositol (PI) but not into polyphosphoinositides in C6 glioma cells with an EC50 of 1.2 X 10(-7) M. The phosphoinositide response was blocked by the 5-HT2 antagonists ketanserin and spiperone but inhibited only partly by methysergide and mianserin. Atropine, prazosin, and yohimbine did not block the response, whereas fluphenazine and haloperidol did so partially but also inhibited basal incorporation by approximately 30%. The 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin did not cause stimulation. Incubation with 5-HT (1 microM) for 1 h increased the incorporation of [2-3H]myoinositol into all phosphoinositides but not into inositol phosphates (IPs). Li+ alone at 10 mM increased labeling in inositol bisphosphate (IP2) and trisphosphate (IP3), whereas labeling in IP and phosphoinositides remained unaltered. Addition of 5-HT had no effect on this increase. Mn2+ at 1 mM enhanced labeling in PI, PI-4-phosphate, lyso-PI, glycerophosphoinositol, and IP, but the presence of 5-HT again did not cause further stimulation. 5-HT also stimulated the release of IPs in cells prelabeled with [2-3H]myo-inositol, incubated with LiCl (10 mM) and inositol (10 mM), and then exposed to 5-HT (1 microM). Radioactivity in IP2 and IP3 was very low, was stimulated approximately 50% as early as 30 s, and remained elevated for at least 20 min. Radioactivity in IP was at least 10 times as high as in IP3 but was increased only from 3 min on with a peak at 20 min, when the elevation was approximately 40 times that in IP3.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of phosphoinositide hydrolysis by serotonin in C6 glioma cells. 302 66

Stable expression of neuronal receptors in cell lines of neural origin is important for studies of neurotransmitter mediated signal transduction. We have achieved this for the first time in three cell lines which are derived from various tissues of neural origin (hippocampus, HN2; chinese hamster brain explant, NCB-20; rat dorsal root ganglion, F-11). Following electroporation assisted transfer of a construct containing the hippocampal serotonin 5-HT1A receptor (5-HT1AR) DNA, one neural cell line, NG-108-15 (murine neuroblastoma x C6 glioma), failed to express the transfected activity, while three others as well as the non-neural CHO (chinese hamster ovary) cells expressed high levels of the receptor. Upon normalization to coexpressed human beta-hexosaminidase B activity, it was found that the human 5-HT1AR, which is normally concentrated in the hippocampus and at a lesser density in the brain, was expressed at the highest level (15.7 x 10(4) receptors/cell) in the HN2 followed by the NCB-20 (8.3 x 10(4) receptors/cell), F-11 (4.4 x 10(4) receptors/cell) and lastly the non-neuronal CHO (4.2 x 10(4) receptors/cell) cells. Ten-twelve days after passage, a striking increase in expression of the receptor was observed only in the cell lines of neural origin. By contrast, there was no appreciable increase in expression of the transfected 5-HT1AR in the non-neural CHO cells over time. This late increase in expression was eliminated in cells which had been maintained in low glucose (1 g/L) for the first two days after passage, thus establishing a vital role of glucose in expression of the transfected 5-HT1AR in cell lines of neural origin. In all cases the 5-HT1AR was negatively coupled to adenylate cyclase, as evidenced by an agonist mediated decrease in prostaglandin E1 stimulated cyclic AMP levels.
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PMID:Heterologous expression of the serotonin 5-HT1A receptor in neural and non-neural cell lines. 847 11

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

Expression of seven serotonin or 5-hydroxytryptamine (5-HT) receptors (5-HT1D alpha, 5-HT1E, 5-HT2, 5-HT1A, 5-HT1C, 5-HT1D beta, and 5-HT6) was investigated in human normal fetal astrocytes and eight glioma cell lines by reverse transcription and polymerase chain reaction (RT-PCR). No expression of 5-HT1D beta and 5-HT6 was observed in any of the cell lines studied. The 5-HT1D alpha receptor was found to be expressed in two human glioma cell lines but not in normal astrocytes. In addition, only three glioma cell lines expressed the 5-HT1E receptor. The 5-HT1C receptor was expressed in six glioma cell lines but not in normal astrocytes while the 5-HT1A was found to be expressed in normal astrocytes from the left hemisphere and in six glioma cell lines but not in normal astrocytes from the cerebellum. Interestingly, the 5-HT2 receptor was expressed in all cells studied but very weakly in normal astrocytes. The effect of 5-HT on glioma cell proliferation, migration, and invasion was also investigated. Serotonin was found to positively modulate these three processes in vitro. These results suggest that 5-HT may play an important role in the control of the biological properties of human glioma cells.
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PMID:Expression of serotonin receptors in human fetal astrocytes and glioma cell lines: a possible role in glioma cell proliferation and migration. 888 28

Alniditan is a new migraine-abortive agent. It is a benzopyran derivative and therefore structurally unrelated to sumatriptan and other indole-derivatives and to ergoline derivatives. The action of sumatriptan is thought to be mediated by 5-hydroxytryptamine (5-HT)1D-type receptors. We investigated the receptor-binding profile in vitro of alniditan compared with sumatriptan and dihydroergotamine for 28 neurotransmitter receptor subtypes, several receptors for peptides and lipid-derived factors, ion channel-binding sites, and monoamine transporters. Alniditan revealed nanomolar affinity for calf substantia nigra 5-HT1D and for cloned h5-HT1D alpha, h5-HT1D beta and h5-HT1A receptors (Ki = 0.8, 0.4, 1.1, and 3.8 nM, respectively). Alniditan was more potent than sumatriptan at 5-HT1D-type and 5-HT1A receptors. Alniditan showed moderate-to-low or no affinity for other investigated receptors; sumatriptan showed additional binding to 5-HT1F receptors. Dihydroergotamine had a much broader profile with high affinity for several 5-HT, adrenergic and dopaminergic receptors. In signal transduction assays using cells expressing recombinant h5-HT1D alpha, h5-HT1D beta, or h5-HT1A receptors, alniditan (like 5-HT) was a full agonist for inhibition of stimulated adenylyl cyclase (IC50 = 1.1, 1.3, and 74 nM, respectively, for alniditan). Therefore, in functional assays, the potency of alniditan was much higher at 5-HT1D receptors than at 5-HT1A receptors. We further compared the properties of [3H]alniditan, as a new radioligand for 5-HT1D-type receptors, with those of [3H]5-HT in membrane preparations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [3H]Alniditan revealed very rapid association and dissociation binding kinetics and showed slightly higher affinity (Kd = 1-2 nM) than [3H]5-HT. We investigated 25 compounds for inhibition of [3H]alniditan and [3H]5-HT binding in the three membrane preparations; Ki values of the radioligands were largely similar, although some subtle differences appeared. Most compounds did not differentiate between 5-HT1D alpha and 5-HT1D beta receptors, except methysergide, ritanserin, ocaperidone, risperidone, and ketanserin, which showed 10-60-fold higher affinity for the 5-HT1D alpha receptor. The Ki values of the compounds obtained with 5-HT1D receptors in calf substantia nigra indicated that these receptors are of the 5-HT1D beta-type. We demonstrated that alniditan is a potent agonist at h5-HT1D alpha and h5-HT1D beta receptors; its properties probably underlie its cranial vasoconstrictive and antimigraine properties.
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PMID:Alniditan, a new 5-hydroxytryptamine1D agonist and migraine-abortive agent: ligand-binding properties of human 5-hydroxytryptamine1D alpha, human 5-hydroxytryptamine1D beta, and calf 5-hydroxytryptamine1D receptors investigated with [3H]5-hydroxytryptamine and [3H]alniditan. 896 79

The transcriptional initiation and regulation of the rat serotonin 5-HT1A receptor gene were characterized. By three types of analyses, a single brain-specific site of transcriptional initiation was localized to -967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line. This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element, suggesting TATA-driven transcription of the rat 5-HT1A receptor. To identify the promoter activity of the receptor gene, progressive 5' deletions of the -2,719/-117-bp fragment of the 5-HT1A promoter linked to luciferase gene were transfected into 5-HT1A-negative (pituitary GH4C1, L6 myoblast, and C6 glioma) and 5-HT1A-positive (septal SN-48 and raphe RN46A) cell lines. Enhancer regions were identified within a fragment between nucleotides -426 and -117 that selectively enhanced transcription in 5-HT1A-positive cells. A nonselective enhancer/promoter that mediated expression in all cell lines was located upstream between -1,519 and -426 bp in a DNA segment containing consensus TATA, CCAAT, SP-1, and AP-1 elements as well as a poly-GT26 dinucleotide repeat. Strong repression of transcription in all cell lines was conferred by the region upstream of -1,519 bp that contains a 152-bp DNA segment with >80% identity to RANTES, tumor necrosis factor-beta, and other immune system genes. Our results indicate that TATA-driven expression of the 5-HT1A receptor is regulated by a novel proximal tissue-specific enhancer region, a nonselective promoter, and an upstream repressor region that is distinct from previously identified neuron-specific repressors.
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PMID:TATA-driven transcriptional initiation and regulation of the rat serotonin 5-HT1A receptor gene. 1034 31

The level of expression of the 5-HT1A receptor in the raphe and limbic systems is implicated in the etiology and treatment of major depression and anxiety disorders. The rat 5-HT1A receptor gene is regulated by a proximal TATA-driven promoter and by upstream repressors that inhibit gene expression. Deletion of a 71-base pair (bp) segment between -1590/-1519 bp of the 5-HT1A receptor gene induced over 10-fold enhancement of transcriptional activity in both 5-HT1A receptor-expressing (RN46A raphe and SN48 septal) cells and receptor-negative (L6 myoblast and C6 glioma) cells. A 31-bp segment of the repressor was protected from DNase I digestion by RN46A or L6 nuclear extracts. Within the 31-bp segment, a single protein complex was present in receptor-expressing cells that bound a novel 14-bp DNA element; in receptor-negative cells, an additional complex bound an adjacent 12-bp sequence. In receptor-positive but not receptor-negative cells, mutation of the 14-bp element to eliminate protein binding abrogated repression to nearly the same extent as deletion of the -1590/-1519 bp segment. Additional mutation of both 14-bp and 12-bp elements abolished protein binding and repressor activity in receptor-negative cells. Thus a single protein-DNA complex at the 14-bp element represses the 5-HT1A receptor gene in 5-HT1A receptor-positive neuronal cells, whereas adjacent DNA elements provide a dual repression mechanism in 5-HT1A receptor-negative cells.
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PMID:Novel dual repressor elements for neuronal cell-specific transcription of the rat 5-HT1A receptor gene. 1071 39

The serotonin-1A (5-HT1A) receptor is the primary somatodendritic autoreceptor that inhibits the activity of serotonergic raphe neurons and is also expressed in nonserotonergic cortical and limbic neurons. Alterations in 5-HT1A receptor levels are implicated in mood disorders, and a functional C(-1019)G 5-HT1A promoter polymorphism has been associated with depression, suicide, and panic disorder. We examined the cell-specific activity of identified transcription factors, human nuclear deformed epidermal autoregulatory factor-1 (DEAF-1)-related (NUDR)/Deaf-1 and Hes5, at the 5-HT1A C(-1019) site. In serotonergic raphe RN46A cells, Deaf-1 and Hes5 repressed the 5-HT1A receptor gene at the C(-1019)-allele but not the G(-1019)-allele. However, in nonserotonergic cells that express 5-HT1A receptors (septal SN48, neuroblastoma SKN-SH, and neuroblastoma/glioma NG108-15 cells), Deaf-1 enhanced 5-HT1A promoter activity at the C(-1019)-allele but not the G-allele, whereas Hes5 repressed in all cell types. The enhancer activity of Deaf-1 was orientation independent and competed out Hes5 repression. To test whether Deaf-1 activity is intrinsic, the activity of a Gal4DBD (DNA binding domain)-Deaf-1 fusion protein at a heterologous Gal4 DNA element was examined. Gal4DBD-Deaf-1 repressed transcription in RN46A cells but enhanced transcription in SN48 cells, indicating that these opposite activities are intrinsic to Deaf-1. Repressor or enhancer activities of Deaf-1 or Gal4DBD-Deaf-1 were blocked by histone deacetylase inhibitor trichostatin A. Thus, the intrinsic activity of Deaf-1 at the 5-HT1A promoter is opposite in presynaptic versus postsynaptic neuronal cells and requires deacetylation. Cell-specific regulation by Deaf-1 could underlie region-specific alterations in 5-HT1A receptor expression in different mood disorders.
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PMID:Cell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism. 1646 35