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 (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

A neuronal cell model endogenously expressing the 5-HT1A receptor, in which to study the function and regulation of this gene, has yet to be identified. We examined murine SN-48 cells, a septum x neuroblastoma fusion cell line that proliferates in a nondifferentiated state but can be induced to differentiate into neurofilament-positive cells following 24-96 hr treatment with 10 microM retinoic acid in low serum. Northern blot analysis demonstrated the presence of a single 10.9 kilobase (kb) 5-HT1A receptor RNA species in differentiated SN-48 cells, which was not detected in undifferentiated SN-48 cells. The presence of receptor RNA in differentiated SN-48 cells correlated with the appearance of functional responses (i.e., pertussis toxin-sensitive inhibition of cAMP accumulation) to 5-HT1A agonists in differentiated but not in undifferentiated cells. In order to verify that the large 10.9 kb RNA species in SN-48 cells truly corresponded to the mouse 5-HT1A receptor RNA, a cDNA fragment from differentiated SN-48 cells was used to clone the corresponding mouse brain cDNA. The 2.4 kb cDNA contained a single open reading frame that displayed high (> 85% predicted amino acid identity) homology to the human and rat 5-HT1A receptor genes. When transfected into receptor-negative Ltk- cells, this cDNA was found to direct expression of a murine 5-HT1A receptor. Thus, we conclude that upon differentiation SN-48 cells express RNA encoding functional 5-HT1A receptors. The SN-48 septal cells will provide a useful cellular model system for investigating aspects of neuronal differentiation leading to the development of sensitivity to serotonergic input.
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PMID:Cloning and differentiation-induced expression of a murine serotonin1A receptor in a septal cell line. 825 66

We have used single cell clones of Swiss 3T3 cells transfected with genes for the human 5-HT1A or 5-HT2 receptor to study down-regulation and desensitization. After pre-incubation of the cells with serotonin agonists, a time-dependent decrease in [3H]8-hydroxy-2-(di-n-propylamino) tetralin or [3H]ketanserin binding was observed. The pertussis toxin sensitive, 5-HT mediated inhibition of forskolin-stimulated cAMP accumulation in 5-HT1A receptor transfected cells was diminished by 68% after a 2 h pre-incubation of the cells with 10 microM 5-HT. The pertussis toxin insensitive, 5-HT mediated PI turnover in 5-HT2 receptor transfected cells was decreased by 65% after pre-treatment. While this decrease was paralleled by a decreased potency of 5-HT to stimulate PI turnover, in 5-HT1A cells the potency of 5-HT to inhibit cAMP formation was comparable to control values. The down-regulation and desensitization of the 5-HT2 receptor can be explained by phosphorylation via activated PKC. In contrast, the attenuation of the 5-HT1A receptor-coupled inhibition of cAMP accumulation has to occur by an alternative, as yet unknown, molecular mechanism.
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PMID:Agonist-induced down-regulation of human 5-HT1A and 5-HT2 receptors in Swiss 3T3 cells. 826 Jun 15

1. An inwardly rectifying K+ current activated by serotonin (5-HT) was recorded from acutely isolated adult dorsal raphe (DR) neurones using the whole-cell recording mode of the patch clamp technique. 2. The 5-HT-induced K+ current (I5-HT) was only visible at an [K+]0 > 5 mM and it was observed in 69% of the cells. 3. The reversal potential for I5-HT was close to the potassium equilibrium potential and was shifted by 51 mV per 10-fold change in [K+]0 indicating that I5-HT was carried predominantly by K+. The chord conductance of I5-HT at -90 mV was proportional to the external [K+] raised to a fractional power. 4. A dose-response relationship revealed that I5-HT was activated with an ED50 of 30 nM. Ba2+ (0.1 mM) blocked I5-HT completely. Spiperone reversibly antagonized the response to 5-HT and 8-OHDPAT (8-hydroxy-2-(di-n-propylamino)tetralin) mimicked the response indicating that the receptor activated was of the 5-HT1A subtype. 5. The response to 5-HT was largely prevented by in vitro pretreatment of the cells with pertussis toxin (PTX) indicating the involvement of a PTX-sensitive G-protein in the transduction mechanism. 6. cAMP and lipoxygenase metabolites, both implicated in the modulation of similar currents in other preparations, were found not to alter the effectiveness of 5-HT. 7. Glibenclamide and tolbutamide, blockers of the ATP-regulated K+ channel, did not reduce the effect of 5-HT in DR neurones. 8. These results show that in acutely isolated adult DR neurones 5-HT activates an inwardly rectifying K+ current and this involves a PTX-sensitive G-protein in the transduction pathway which may interact with the K+ channel directly.
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PMID:Whole-cell recordings of inwardly rectifying K+ currents activated by 5-HT1A receptors on dorsal raphe neurones of the adult rat. 827 Dec 4

The injection of 1 microgram of pertussis toxin, which inactivates Gi/o proteins, in the rat dorsal raphe nearly abolished the responsiveness of serotonin (5-HT) neurons to microiontophoretic applications of 5-HT and selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) without altering their responsiveness to of gamma-aminobutyric acid (GABA). In contrast, the injection of 1 microgram of cholera toxin, which causes an activation of Gs proteins, did not alter the responsiveness of 5-HT neurons to 5-HT, 8-OH-DPAT or GABA. Such in situ injection of either toxin in the dorsal hippocampus decreased by about 90% the responsiveness of CA3 pyramidal neurons to microiontophoretic applications onto their cell body of 5-HT and 8-OH-DPAT, but not of GABA. The effectiveness of the stimulation of the ascending 5-HT pathway in suppressing the firing activity of the same neurons, which results from the release of 5-HT at the level of their dendritic tree, was also markedly decreased in the cholera toxin-treated rats, but intriguingly not in the pertussis toxin-treated rats. These results indicate that, on 5-HT neurons, the somato-dendritic 5-HT1A autoreceptor is coupled to Gi/o, but insensitive to the persistent activation of Gs proteins. In the CA3 region of the hippocampus, there would be two subsets of postsynaptic 5-HT1A receptors on the pyramidal neurons: those apposed to 5-HT terminals on their dendritic tree (denoted intrasynaptic) and those located on their cell body (denoted extrasynaptic). The former are cholera toxin sensitive, whereas the latter are sensitive to both pertussis and cholera toxins.
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PMID:Differential properties of pre- and postsynaptic 5-hydroxytryptamine1A receptors in the dorsal raphe and hippocampus: II. Effect of pertussis and cholera toxins. 847 3

Our study was undertaken to characterize the functional properties of 5-hydroxytryptamine (5-HT)1D receptors in the rat midbrain raphe nuclei. In a first series of experiments, designed to assess whether 5-HT1D receptors are coupled to Gi/o proteins, the intracerebral injection of pertussis toxin into the dorsal raphe as well as incubation of midbrain raphe slices with the alkylating agent N-ethyl-maleimide (NEM) reduced the efficacy of the 5-HT1B/1D agonist sumatriptan to inhibit the electrically evoked overflow of [3H]5-HT from preloaded slices. Furthermore, preincubation with NEM also reduced the efficacy with which the 5-HT1B/1D antagonist GR 127935 enhanced evoked overflow of [3H]5-HT. These results indicate that, in rat midbrain raphe nuclei, 5-HT1D receptors are linked to Gi/o proteins. In an attempt to determine whether 5-HT1D receptors are located on 5-HT neurons, the inhibitory effect of sumatriptan and of the nonselective 5-HT agonist 5-carboxyamidotryptamine on K(+)-evoked overflow of [3H]5-HT was assessed in the presence of the Na+ channel blocker tetrodotoxin. Neither the inhibitory effect of sumatriptan nor that of 5-carboxyamidotryptamine were reduced by the addition of tetrodotoxin to the superfusion medium, suggesting that these 5-HT1D receptors are located on 5-HT neurons and may be considered autoreceptors. In a third series of experiments, rats were treated for 21 days either with the selective 5-HT reuptake inhibitor paroxetine (10 mg/kg/day, s.c.) or the reversible type A monoamine oxidase inhibitor befloxatone (0.75 mg/kg/day, s.c.) and superfusion experiments were performed after a 48-hr washout period. 5-HT1D receptors, similarly to 5-HT1A autoreceptors, desensitize after long-term treatment with a selective 5-HT reuptake inhibitor or a reversible type A monoamine oxidase inhibitor because the efficacy of sumatriptan and of 8-OH-DPAT to inhibit the electrically evoked overflow of [3H]5-HT was reduced after the administration of either drug.
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PMID:Regulation of 5-hydroxytryptamine release from rat midbrain raphe nuclei by 5-hydroxytryptamine1D receptors: effect of tetrodotoxin, G protein inactivation and long-term antidepressant administration. 863 39

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

1. Whole-cell Ca2+ currents (ICa) from cultured rat melanotrophs were identified by their sensitivity to Ca2+ channel blockers, and their modulation by serotonin (5-HT) was studied. All cells displayed high voltage-activated (HVA; > -30 mV) Ca2+ currents. A low voltage-activated (LVA; > -60 mV) Ca2+ current was detected in 92% of the cells. 2. The whole-cell ICa was insensitive to omega-conotoxin GVIA (0.5-1 microM) indicating the absence of N-type Ca2+ channels. 3. At a holding potential (Vh) of -70 mV, the L-type channel blocker nifedipine reduced ICa in a dose-dependent manner with a half-maximal effective concentration (IC50) of 28 nM. The L-type current represented 39% of the total ICa. 4. omega-Agatoxin IVA (omega-Aga IVA) produced a biphasic dose-dependent inhibition of ICa, with IC50 values of 0.4 and 91 nM, indicating the presence of P-type and Q-type Ca2+ channels, which accounted respectively for 16 and 45% of the total ICa. The P-type current was also blocked by synthetic funnel-web spider toxin (sFTX 3.3; 1-10 microM) and was present only in a subpopulation (60-70%) of cells. 5. All cells possessed a Ca2+ current which was resistant to nifedipine (10 microM) and omega-Aga IVA (50 nM). This current was not affected by Ni2+ (40 microM) but was abolished by a low concentration of Cd2+ (10 microM) and by omega-conotoxin MVIIC (1 microM) indicating that it was a Q-type Ca2+ current. 6. 5-HT (10 microM) inhibited the whole-cell ICa in 70% of the cells tested (n = 120) by activating 5-HT1A and 5-HT2C receptors. 5-HT produced either a kinetic slowing of the activation phase (37% of the cells) or a scaling down (14% of the cells) of ICa. In the majority of cells (49%) both types of inhibition were found to coexist. 7. The effects of 5-HT were voltage dependent, rendered irreversible when GTP-gamma-S (30 microM) was present in the pipette solution and abolished by pretreatment of the cells with pertussis toxin (PTX; 150 ng ml-1, 18 h). 8. Low concentrations of omega-Aga IVA (20 nM), which blocked mainly P-type channels, did not reduce the effect of 5-HT on ICa. The scaling down effect of 5-HT on ICa was eliminated in the presence of nifedipine (10 microM) and the kinetic slowing effect of 5-HT persisted after blockade of L- and P-type channels but was abolished by omega-conotoxin MVIIC (1 microM). 9. We conclude that rat melanotrophs possess functional L-, P- and Q-type Ca2+ channels and that 5-HT inhibits selectively L-type and Q-type Ca2+ currents with different modalities. These effects are voltage dependent and mediated by a PTX-sensitive G-protein.
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PMID:Selective inhibition of high voltage-activated L-type and Q-type Ca2+ currents by serotonin in rat melanotrophs. 868 60

We used standard intracellular current-clamp electrophysiological recording techniques in a brain slice preparation to determine whether chronic cocaine administration would: 1) alter the sensitivity of septal neurons to exogenous serotonin (5-HT) application and 2) modify the interaction of 5-HT with cocaine in vitro. Recordings were made from neurons in rat brain slices that contained the dorsolateral septal nucleus obtained from drug naive (DN) rats or rats give cocaine (15mg/kg, i.p., 2 X daily) for periods of 7 (CC7) or 14 (CC14) days. In addition, some of these rats also received intraventricular pertussis toxin (PTX) injections 2 to 3 days before experimentation to abolish the postsynaptic 5-HT1A receptor-mediated membrane hyperpolarization and to unmask a 5-HT-induced depolarization. In comparison with DN and CC7, CC14 slices showed an increased sensitivity to 5-HT as revealed by a 2-fold leftward shift in the 5-HT EC50 values. In addition, in PTX-CC14 slices, 5-HT could hyperpolarize the cell membrane, whereas the 5-HT1A agonist, 8-OH-DPAT, and the gamma-aminobutyric acidB agonist, baclofen, failed to do so. We also observed that cocaine (3 microM) in CC14 slices did not significantly potentiate and prolong 5-HT hyperpolarizations as found in DN slices. We conclude that in the CC14 septal slice a 5-HT transporter is down-regulated and that an atypical 5-ht response can be elicited. Additionally, 5-HT1A receptor up-regulation and/or 5-HT2 receptor down-regulation may contribute to the increased sensitivity of septal neurons to 5-HT.
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PMID:Modification of serotonin responses in rat dorsolateral septal nucleus neurons by acute and chronic cocaine. 878 62

The mechanisms through which presynaptic 5-HT1A receptors cause inhibition of acetylcholine release from the guinea pig myenteric plexus were investigated. The selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and 5-hydroxytryptamine (5-HT) caused concentration-dependent inhibitions of the electrically evoked release of [3H]acetylcholine from myenteric plexus preparations that had been preincubated with [3H]choline. The inhibitory effects were not modified by the activator of adenylyl cyclase, forskolin (10 microM), the phosphodiesterase inhibitor, AH 21-132 (100 microM), or after pretreatment of the guinea pigs with pertussis toxin (60 micrograms/kg). In contrast, the protein kinase C activator 4 beta- phorbol-12,13-dibutyrate (0.1 microM) prevented the release-inhibiting effect of 8-OH-DPAT, whereas the inactive isomer 4 alpha-phorbol-12,13-dibutyrate (0.1 microM) was without effect. The results suggest that the presynaptic 5-HT1A receptor is not coupled to a pertussis toxin sensitive G protein or to adenylyl cyclase. However, protein kinase C seems to be involved in the mechanism of inhibition of acetylcholine release by presynaptic 5-HT1A receptors.
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PMID:5-HT1A receptor-mediated inhibition of acetylcholine release from guinea pig myenteric plexus: potential mechanisms. 879 11


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