UNIPROT:P08908 - FACTA Search

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Query: UNIPROT:P08908 (5-HT1A)
5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian circadian clock located in the suprachiasmatic nuclei (SCN) continues to oscillate when isolated in a brain slice preparation, and can be phase shifted in vitro by a variety of serotonergic (5-HTergic) agents. We have previously shown that 5-HT and a 5-HT agonist, quipazine, induce phase advances in the daytime and phase delays at night; the phase advances are mimicked by the 5-HT1A-selective agonist 8-OH-DPAT, by analogs of cyclic AMP, and by treatments that increase endogenous levels of cyclic AMP. Here we investigated the intracellular pathway through which these daytime phase advances occur. We find that quipazine- and 8-OH-DPAT-induced phase advances are blocked by two inhibitors of the cyclic AMP-dependent protein kinase, PK-A (H8 and Rp-cAMPS) as well as by a variety of K+ channel blockers (BaCl2, apamin, and charybdotoxin). Furthermore, we confirm previous work showing that a cyclic AMP analog induces phase advances in the daytime, and show that these phase advances are also blocked by BaCl2 and apamin. Finally, we show that a K+ ionophore induces similar phase advances in the subjective day, and these phase advances are blocked by Rp-cAMPS. These results indicate that both activation of PK-A and opening of K+ channels are necessary for 5-HT-induced phase advances of the SCN circadian clock. We propose a model that can account for our results.
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PMID:Serotonergic phase advances of the mammalian circadian clock involve protein kinase A and K+ channel opening. 803 50

In vivo microdialysis was used to examine the efflux of cyclic AMP (cAMP) into the extracellular fluid of the ventral hippocampus in the freely moving rat. The changes in extracellular cAMP concentration were monitored in response to forskolin and the serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The basal level of hippocampal extracellular cAMP was 2.3 +/- 0.2 pmol/ml (n = 6), after a 3-h postsurgery stabilisation period. Perfusion of forskolin (100 microM) through the probe for 30 min significantly increased the efflux of cAMP, which returned to baseline levels within 90 min. 8-OH-DPAT (0.3 mg/kg s.c.) also significantly increased cAMP efflux, whereas a similar volume of saline had no effect. Desensitisation of the 8-OH-DPAT-induced increase in cAMP efflux was observed following a second administration of 8-OH-DPAT after a 4-h interval. Administration of 8-OH-DPAT did not alter the efflux of cAMP when forskolin was perfused through the probe. Pretreatment with WAY 100135 [N-tert-butyl 3-4-(2-methoxyphenyl)piperazine-1-yl-2-phenylpropanamide dihydrochloride] (5 mg/kg s.c.), a specific 5-HT1A receptor antagonist, prevented the 8-OH-DPAT-induced increase in cAMP efflux. The data indicate that the 8-OH-DPAT-induced increase in cAMP efflux in vivo is mediated by a 5-HT1A receptor.
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PMID:Serotonin 5-HT1A receptor activation increases cyclic AMP formation in the rat hippocampus in vivo. 815 32

5-Hydroxytryptamine (5-HT) is a mitogen for selected cell types. We have reported that 5-HT is an autocrine growth factor for functioning human pancreatic carcinoid (BON) cells; autocrine growth effect is transmitted by 5-HT1A but not 5-HT1C/2 receptors, activation of which decreases cyclic AMP production through a pertussis toxin-sensitive inhibitory GTP-binding protein. In this study, the effect of 5-HT3 receptor antagonist, ondansetron, on BON was examined. Ondansetron did not affect growth of BON cells and also affected neither stimulation of phosphatidylinositol hydrolysis or inhibition of cyclic AMP production evoked by 5-HT in BON cells. Ondansetron, however, inhibited mobilization of intracellular calcium evoked by 5-HT. Present findings suggest that BON cells possess 5-HT3 receptors, but their roles in pancreatic carcinoid cells are still unknown.
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PMID:Effect of 5-HT3 receptor antagonist (ondansetron) on functioning human pancreatic carcinoid cells. 825 12

Serotonin (5-hydroxytryptamine, 5-HT) reduces forskolin-induced stimulation of cyclic AMP in rabbit iris-ciliary body (ICB) homogenates. The effect is dose dependent and can be mimicked by a number of 5-HT1 receptor agonists including 5-carboxamidotryptamine (5-CT) and RU 24969 [5-methoxy-3-(1,2,3,6, tetrahydro-4-pyridinyl)-1-indole]. The inhibitory effects of 5-CT and the 5-HT1A selective agent 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) on forskolin stimulated adenylate cyclase activity are greater in isolated ciliary processes than in the iris musculature. Spiperone and propranolol significantly antagonize the action of 5-CT in the iris-ciliary body, while ketanserin (5-HT2 antagonist) and ICS 205930 (5-HT3/4 blocker) were without influence, indicating the presence of the 5-HT1A subtype of receptor. Studies carried out on human ICB homogenates also suggest the presence of 5-HT1A-like receptors, although these receptors are not identical to those in rabbit. Similarities include dose-dependent decreases in cAMP levels stimulated by forskolin elicited by 1-(3-chlorophenyl) piperazine (mCPP), 5-CT and 8-OH-DPAT. Moreover, the inhibitory effect of 5-CT can also be significantly reduced by the 5-HT1 receptor antagonist, propranolol. However, unlike the case of rabbit tissue, spiperone was ineffective in abolishing the 5-CT response in human ICB homogenates.
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PMID:The presence of serotonin (5-HT1) receptors negatively coupled to adenylate cyclase in rabbit and human iris-ciliary processes. 840 87

Recently, a 5-hydroxytryptamine (5-HT) receptor has been described, whose pharmacology was distinct from that of the already known serotonergic receptors, so that it has been called 5-HT4. Because the lack of a high affinity radioligand, the identification of this receptor depends entirely on functional pharmacological analysis. Its stimulation leads to an increase in cyclic AMP accumulation in mouse embryo colliculi neurons, in guinea pig hippocampus and in human heart. We studied the effect of two indoleamines, 5-HT and 5-methoxytryptamine (5-MeO-T), and a benzimidazolone derivative, BIMU 8, in stimulating basal adenylyl cyclase activity in human frontal cortex, and characterized the receptor subtype involved. In membranes prepared from this tissue, 5-HT, 5-MeO-T and BIMU 8 dose-dependently stimulated (13-25%) the basal enzyme activity (220 pmoles cyclic AMP/min/mg protein). 5-MeO-T behaved as a full agonist, BIMU 8 elicited about 60% of the maximal 5-HT effect. The selective 5-HT1A agonist 8-OH-DPAT, was devoid of any stimulating activity. ICS 205-930, a low affinity 5-HT4 receptor antagonist, completely reversed the effect of all three agonists at high concentrations. Therefore, the present data are consistent with the 5-HT-mediated stimulation of adenylyl cyclase in human frontal cortex resulting by the activation of a 5-HT4 receptor subtype.
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PMID:Pharmacological characterization of the 5-hydroxytryptamine receptor coupled to adenylyl cyclase stimulation in human brain. 843 6

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

The involvement of serotonin 5-HT1D beta receptor sites was investigated in the growth of rat C6 glial cells permanently transfected with a gene encoding a human 5-HT1D beta receptor. The 5-HT receptor identity of control and transfected C6 glial/5-HT1D beta cells was determined by reverse transcription-polymerase chain reaction using primers specific for rat 5-HT1A, rat 5-HT1B, rat 5-HT1D alpha, human 5-HT1D beta, and rat 5-HT2A receptor genes. Constitutive mRNA for 5-HT2A receptors was present in control and transfected C6 glial/5-HT1D beta cells, whereas mRNA for 5-HT1D beta receptor sites was only present in the transfected C6 glial/5-HT1D beta cell line. 5-HT inhibited forskolin-stimulated cyclic AMP formation and promoted cell growth, in contrast to the absence of any measurable effect in pcDNA3 plasmid-transfected and nontransfected C6 glial cells. The 5-HT effects could be mimicked by sumatriptan (EC50 = 44-76 nM) and were totally and partially blocked by methiothepin (IC50 = 9 nM) and GR 127,935 (2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide; IC50 = 97 pM), respectively. No effect on cell growth was measured with the 5-HT2 receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; 10 microM], suggesting that 5-HT2A receptors are not involved in the 5-HT-stimulated C6 glial/5-HT1D beta cell growth. Dibutyryl-cyclic AMP (0.3 mM)-treated cultures did not show sumatriptan-promoted cell growth, indicating an inhibitory role for cyclic AMP in the cell growth mediated by 5-HT1D beta receptor sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of cloned human serotonin 5-HT1D beta receptor sites in stably transfected C6 glial cells promotes cell growth. 852 91

In this study, it has been clearly demonstrated that a selective 5-hydroxytryptamine (5-HT)1A agonist, 8-OH-2-(di-n-propylamino)-tetraline (8-OH-DPAT, 1 microM) significantly inhibited forskolin (10 microM)-stimulated cyclic AMP (cAMP) accumulation in the C6BU-1 cells transfected with 5-HT1A receptor gene. Further, this 8-OH-DPAT-induced inhibition of forskolin-stimulated activity was significantly attenuated after pre-exposure to 5-HT (10 microM) for 12 h. Spiperone (10 microM), a 5-HT1A and 5-HT2A antagonist, prevented 5-HT-induced desensitization of 5-HT1A receptor, but a selective 5-HT2A receptor antagonist, ketanserin, did not. In addition, pre-exposure to a selective 5-HT2A agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 10 microM), for 24 h did not alter the inhibitory effect of 8-OH-DPAT on forskolin-stimulated cAMP accumulation in these transfected cells, suggesting that prolonged exposure to 5-HT induced 5-HT1A receptor desensitization, mediated by 5-HT1A receptor but not 5-HT2A receptors.
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PMID:Serotonin-induced 5-HT1A receptor desensitization in C6BU-1 glioma cells transfected with 5-HT1A receptor gene. 857 95

The RN46A cell line was derived from embryonic day 13 rat medullary raphe cells by infection with a retrovirus encoding the temperature-sensitive mutant of SV40 large T antigen (tsT-ag). The RN46A cell line is neuronally restricted and constitutively differentiates following a shift to nonpermissive temperature. Differentiated RN46A cells express low levels of tryptophan hydroxylase (TPH) but no detectable levels of serotonin (5-HT). Treatment of cultures with the adrenocorticotropic hormone peptide ACTH4-10 up-regulates the expression of TPH immunoreactivity in differentiated RN46A cells, but 5-HT synthesis requires initial treatment with ACTH4-10, followed by partial membrane depolarizing conditions. Up-regulation of TPH by ACTH4-10 is apparently due to activation of adenylate cyclase, whereas the increased 5-HT synthesis with membrane depolarization can be blocked with the voltage-sensitive Ca(2+)-channel blockers nifedipine and omega-conotoxin. ACTH4-10 treatment also markedly up-regulates the expression of the 5-HT reuptake transporter, as do dibutyryl cyclic AMP and forskolin; chronic membrane depolarization has no effect on 5-HT reuptake. The expression of the high-affinity 5-HT1A receptor is increased threefold by ACTH4-10 treatment during differentiation and fivefold by differentiation under partial membrane depolarizing conditions. Combining ACTH4-10 treatment and membrane depolarization does not increase expression of the 5-HT1A receptor further. 5-HT release is constitutive in ACTH-treated RN46A cells and linked to spontaneous synaptic vesicle fusion in RN46A cells. Considered with previous results, these data indicate that multiple effectors, ACTH, brain-derived neurotrophic factor, and membrane depolarization, have both distinct and overlapping effects that regulate specific elements of the serotonergic neuronal phenotype during differentiation and maturation.
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PMID:Adrenocorticotropic hormone activation of adenylate cyclase in raphe neurons: multiple regulatory pathways control serotonergic neuronal differentiation. 859 7

1. Chinese hamster ovary cells (CHO-K1) express an endogenous 5-hydroxytryptamine (5-HT)1B-like receptor that is negatively coupled to adenylyl cyclase through a pertussis toxin (PTX)-sensitive mechanism. Furthermore, the human adenosine A1 receptor when expressed in CHO-K1 cells (CHO-A1) has been shown to mobilize intracellular Ca2+ through a PTX-sensitive mechanism. Therefore the aim of this investigation was to determine whether the endogenous 5-HT1B-like receptor was able to stimulate increases in intracellular free [Ca2+] ([Ca2+]i) in CHO-A1 cells. 2. In agreement with previous studies using CHO cells, 5-hydroxytryptamine (5-HT) elicited a concentration-dependent inhibition of forskolin-stimulated [3H]-cyclic AMP production in CHO-A1 cells (p[EC50] = 7.73 +/- 0.13). 5-HT (1 microM) inhibited 47 +/- 5% of the [3H]-cyclic AMP accumulation induced by 3 microM forskolin. Forskolin stimulated [3H]-cyclic AMP accumulation was also inhibited by the 5-HT1 receptor agonists (p[EC50] values) 5-carboxyamidotryptamine (5-CT; 8.07 +/- 0.08), RU 24969 (8.12 +/- 0.33) and sumatriptan (5.80 +/- 0.31). 3. 5-HT elicited a concentration-dependent increase in [Ca2+]i in CHO-A1 cells (p[EC50] = 8.07 +/- 0.05). In the presence of 2 mM extracellular Ca2+, 5-HT (1 microM) increased [Ca2+]i from 174 +/- 17 nM to 376 +/- 22 nM. The 5-HT1 receptor agonists (p[EC50] values), 5-carboxyamidotryptamine (5-CT; 7.9 +/- 0.02), RU 24969 (8.1 +/- 0.07) and sumatriptan (5.9 +/- 0.11) all elicited concentration-dependent increases in [Ca2+]i. Similar maximal increases in [Ca2+]i were obtained with each agonist. The selective 5-HT1A receptor agonist, 8-OH-DPAT (10 microM) did not stimulate increases in [Ca2+]i. 5-HT (100 microM) and 5-CT (10 microM) did not stimulate a measurable increase in [3H]-inositol phosphate accumulation in CHO-A1 cells. 4. 5-HT (1 microM)-mediated increases in [Ca2+]i were insensitive to the 5-HT receptor antagonist, ritanserin (5-HT2; 100 nM), ketanserin (5-HT2; 100 nM), LY-278,584 (5-HT3; 1 microM) and WAY 100635 (5-HT1A; 1 microM). The response to 5-HT (100 nM) was antagonized by the non-selective 5-HT1 antagonist, methiothepin (pKb = 8.90 +/- 0.09) and the 5-HT1D antagonist GR 127935 (pKb = 10.44 +/- 0.06). 5. Pretreatment with PTX (200 ng ml-1 for 4 h) completely attenuated the Ca2+ response to 100 microM 5-HT. 6. In untransfected CHO-K1 cells, 5-HT (1 microM), RU 24969 (1 microM), and 5-CT (1 microM) elicited increases in [Ca2+]i similar to those observed in CHO-A1 cells. 7. These data demonstrate that in CHO-K1 cells the endogenously expressed 5-HT1B-like receptor couples to the phospholipase C/Ca2+ signalling pathway through a PTX-sensitive pathway, suggesting the involvement of Gi/Go protein(s).
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PMID:Coupling of an endogenous 5-HT1B-like receptor to increases in intracellular calcium through a pertussis toxin-sensitive mechanism in CHO-K1 cells. 868 Jul 21

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