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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CRF is produced in the Leydig cells and acts as a negative autocrine regulator of Leydig cell function. To clarify the hormonal control of CRF secretion by Leydig cells, we evaluated the participation of serotonin (5HT) and serotonin agonists in the release of CRF from Leydig cells and their effects on hCG-induced cAMP generation and steroidogenesis. Serotonin stimulated CRF secretion up to 4-fold above basal levels and inhibited basal and hCG-stimulated cAMP generation and testosterone production (ID50, 1 nM). The inhibitory action of 5HT was prevented by a CRF antibody and the alpha-helical CRF-(9-41) antagonist. The selective 5HT2 receptor agonist (+-)1-[2,5-dimethoxy-4-iodophyryl]2-amino propane hydrochloride (DOI) also stimulated CRF secretion and inhibited hCG-stimulated cAMP generation and testosterone production to control levels (ID50, 7 microM). Serotonergic 5HT1A, 5HT1B/1C, 5HT1D, and 5HT3/5HT2 agonists were less effective inhibitors of hCG-stimulated cAMP and testosterone production, while agonists for the 5HT3 receptor had no effect. [125I]DOI binding studies in Leydig cells demonstrated two sets of receptors with Kd values in the nanomolar and micromolar range, with low and high capacities, respectively. The low affinity site differed from that of brain receptors (Kd, 4.2 nM) and displayed higher binding capacity (50-fold). The selective 5HT2 receptor antagonist ketanserin prevented CRF stimulation and blocked the inhibitory actions of 5HT and DOI, while the alpha 1-adrenergic antagonist prazosin had no effect. Also, treatment of cells with ketanserin increased sensitivity to hCG and raised maximal cAMP and testosterone production. 5HT was a more effective stimulus than hCG in stimulating CRF secretion, and gonadotropin-induced CRF release was inhibited by ketanserin. Inhibitory effects of exogenous CRF were demonstrable after blockade of 5HT action by ketanserin. The inhibitory actions of 5HT were unaffected by pertussis and cholera toxins and were reversed by the addition of 8-bromo-cAMP. These results demonstrate that 5HT acts on 5HT2 receptors in Leydig cells that are distinct from those in the brain to stimulate CRF secretion through a pertussis toxin-insensitive G-protein. This action of 5HT is predominantly mediated by the low affinity 5HT2-binding site and requires full occupancy for maximal CRF stimulation, indicating the absence of spare receptors. 5HT-stimulated CRF inhibits basal and hCG-induced cAMP generation and steroidogenesis. Furthermore, 5HT mediates the stimulatory action of LH/hCG on CRF secretion from Leydig cells and, thus, participates in a negative autoregulatory loop to limit the testosterone response to the gonadotropic stimulus.
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PMID:Regulation of corticotropin-releasing factor secretion from Leydig cells by serotonin. 131 25

The effect of heat-stable E. coli enterotoxin on intestinal fluid secretion is commonly considered to be mediated by stimulation of mucosal cyclic guanosine monophosphate (cGMP). It was demonstrated recently that 5-hydroxytryptamine (5-HT) acts as an important mediator in cholera toxin-induced fluid secretion. To elucidate the possible involvement of 5-HT in the secretory response to heat-stable E. coli enterotoxin, in vivo experiments were performed in the rat jejunum. The inhibitory effects of the 5-HT2 receptor antagonist ketanserin, the 5-HT3 receptor antagonist tropisetron and indomethacin were studied in heat-stable E. coli enterotoxin-induced fluid secretion. Tropisetron and ketanserin (100 micrograms/kg each) alone only partially reduced the secretory effect of the toxin. However, in combination, the two blockers (100 plus 100 micrograms/kg) significantly reduced and at 200 plus 200 micrograms/kg totally abolished heat-stable E. coli enterotoxin-induced secretion without influencing the enterotoxin-induced increase in cGMP. Pretreatment with indomethacin (10 mg/kg) reduced the secretory response to the enterotoxin by about 50%. These results support the concept that 5-HT is an important mediator in intestinal fluid secretion induced by heat-stable E. coli enterotoxin. The enterotoxin may use 5-HT to stimulate prostaglandin formation via 5-HT2 receptors and to activate neuronal structures via 5-HT3 receptors.
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PMID:5-HT receptor antagonists and heat-stable Escherichia coli enterotoxin-induced effects in the rat. 133 Jun 11

The effects of several 5-hydroxytryptamine (5-HT) receptor antagonists were tested in rats in vivo on the intestinal fluid secretion evoked by cholera toxin. Five receptor antagonists were used, namely 2-bromolysergic acid diethylamine (2-bromo-LSD), granisetron, ketanserin, methysergide and ondansetron. The drugs were used in doses that inhibited the arterial hypertension and/or bradycardia evoked by 5-HT given i.v. Granisetron and ondansetron markedly diminished cholera-toxin-evoked secretion, whereas ketanserin was without any effect. Methysergide also diminished cholera-toxin-induced fluid secretion particularly when the drug was given as an i.v. infusion. The results are considered in relation to the pathophysiology of cholera secretion and to the current views of receptor subtypes for 5-HT. It is proposed that the receptor involved is a 5-HT3 receptor, possibly also a receptor of the 5-HT1 type. Results from experiments in which 5-HT (20 mM) was placed in the intestinal lumen to evoke an intestinal secretion suggest that the 5-HT3 receptor is located in the villus tissue. It was also demonstrated that zimeldine, an inhibitor of presynaptic 5-HT reuptake, diminished choleraic secretion, an effect that may be ascribed to a 5-HT tachyphylaxis caused by an accumulation of 5-HT in a synaptic cleft.
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PMID:Actions of serotonin antagonists on cholera-toxin-induced intestinal fluid secretion. 135 26

1. Tight-seal voltage-clamp techniques were used to study the 5-HT3 receptor of differentiated NG108-15 cells. 2. The inward current caused by 5-HT was dependent on the 5-HT concentration: the apparent dissociation constant was 3.3 microM and the Hill coefficient was 1.8. 3. Immediately after establishing a recording, sustained application of a saturating concentration of 5-HT caused the response to decline with a half-time of 0.57 s (at a membrane potential of -70 mV). The time course of desensitization was best fitted by a sum of two exponentials. 4. Desensitization became slower during the first 10 min of recording in the whole-cell configuration, with the half-time for response decay increasing to 1.8 s. The deceleration of desensitization may result from wash-out of a cytoplasmic regulator of the receptor. 5. Desensitization declined less during whole-cell recordings when patch pipettes contained non-hydrolysable analogues of adenosine 5'-triphosphate. 6. Desensitization developed more rapidly following the addition of forskolin, prostaglandin E1, cholera toxin or 1,9-dideoxyforskolin to the recording medium. Non-hydrolysable adenosine 5'-phosphate analogues had no effect on the enhancement of desensitization induced by forskolin.
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PMID:Activation and desensitization of the 5-HT3 receptor in a rat glioma x mouse neuroblastoma hybrid cell. 164 31

5-Hydroxytryptamine (5-HT) is present throughout the gastrointestinal tract, which acts as the major reservoir of this substance in the body. Its physiologic role has not been clearly established, although it seems likely that 5-HT is involved in the regulation of aspects of intestinal motility such as peristalsis and the migrating motor complex. In disease states the contribution of 5-HT is perhaps more clearly established, particularly its role in chemotherapy-induced emesis, in the carcinoid syndrome, and, possibly, in mediating the effect of some intestinal secretagogues, notably cholera toxin. Many of the functions of 5-HT in the gut have been elucidated as a result of the development of antagonists to 5-HT receptors. However, some of these compounds have 5-HT agonist activity as well as 5-HT receptor blocking activity, making interpretation of their effects in health and disease difficult. Nevertheless, 5-HT receptor antagonists are finding an important place in the management of the carcinoid syndrome and in chemotherapy-induced emesis and may well evolve as important agents for modulating gut motility and for inhibiting secretory states in the small and large intestine. The suggestion that 5-HT3 receptor antagonists might also modulate visceral sensation in the gut is of great interest because of their potential to relieve symptoms of functional bowel disorders such as pain, urgency, and bowel frequency.
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PMID:5-Hydroxytryptamine and 5-hydroxytryptamine-3 receptor antagonists. 177 47

The mechanisms of diarrhea in Asiatic cholera have been studied extensively. Cyclic adenosine monophosphate, 5-hydroxytryptamine (5-HT), prostaglandins, and the function of neuronal structures have been implicated in the pathogenesis of cholera. To elucidate the action of 5-HT in mediating cholera secretion, in vivo experiments were performed in the rat jejunum. The inhibitory effects of the 5-HT2 receptor antagonist ketanserin and the 5-HT3 receptor antagonist ICS 205-930 were studied in cholera toxin- and 5-HT-induced fluid secretion. Both ketanserin and ICS 205-930 dose-dependently but only partially reduced the secretory effect of cholera toxin. The combination of the two blockers totally abolished cholera toxin-induced secretion without any influence on cholera toxin-induced increase in cyclic adenosine monophosphate. Prostaglandin E2- and bisacodyl-induced secretion was not affected by the combined administration of 5-HT2 and 5-HT3 antagonists. The present results provide evidence for an important role of 5-HT in cholera toxin-induced secretion. The data suggest a model in which cholera toxin may initiate the release of 5-HT from enterochromaffin cells. 5-Hydroxytryptamine may then cause prostaglandin E2 formation via 5-HT2 receptors and activation of neuronal structures via 5-HT3 receptors. These two effects may finally lead to the profuse fluid secretion which can be totally blocked by the combination of a 5-HT2 blocker and a 5-HT3 blocker.
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PMID:5-HT2 and 5-HT3 receptor subtypes mediate cholera toxin-induced intestinal fluid secretion in the rat. 234 45

Cholera toxin and Escherichia coli heat labile toxin (LT) induced intestinal secretion has in the past been attributed exclusively to an increase in intracellular cAMP whereas E coli heat stable toxin (ST) induced secretion is mediated through cGMP. Evidence is accumulating on the importance of 5-hydroxytryptamine (5-HT) in cholera toxin induced secretion, but its role in LT and ST is not well established. This study therefore investigated in vivo the effect of 5-HT3 receptor antagonist, granisetron, on intestinal fluid and electrolyte secretion induced by cholera toxin, LT, and ST. Granisetron (30, 75, 150, or 300 micrograms/kg) was given subcutaneously to adult male Wistar rats 90 minutes before instillation of 75 micrograms cholera toxin or 50 micrograms LT in isolated whole small intestine. In situ small intestinal perfusion was performed with an iso-osmotic plasma electrolyte solution (PES) to assess fluid movement. In a second group of animals, granisetron (300 micrograms/kg) was given subcutaneously and two hours later small intestinal perfusion with PES containing 200 micrograms/l ST was performed. Cholera toxin induced net fluid secretion (median -50.1 microliters/min/g (interquartile range -59.5 to -29.8)) was found to be dose dependently decreased or abolished by granisetron (plateau effect at 75 micrograms/kg: 18 (-7.8 to 28), p < 0.01). Granisetron in high dose (300 micrograms/kg), however, failed to prevent LT or ST induced secretion (-52 (-121 to -71) v -31 (-44 to -18), and (-39 (-49 to 17) v (-22 (-39 to -3)), respectively). Sodium and chloride movement paralleled that of fluid. In conclusion, these data show that 5-HT and 5-HT3 receptors play an important part in cholera toxin induced secretion but are not involved in E coli heat stable or heat labile toxin induced secretion.
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PMID:Role of 5-hydroxytryptamine type 3 receptors in rat intestinal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins. 759 Apr 28

1. 5-Hydroxytryptamine (5-HT) has been shown to induce contraction of tracheal smooth muscle. However, the mechanisms of action of 5-HT are not known. We therefore investigated the effects of 5-HT on phospholipase C (PLC)-mediated phosphoinositide (PI) hydrolysis and its regulation in canine cultured tracheal smooth muscle cells (TSMCs) labelled with [3H]-inositol. 5-HT-induced inositol phosphates (IPs) accumulation was time- and dose-dependent with a half-maximal response (EC50) and a maximal response at 0.38 +/- 0.05 and 10 microM, respectively. 2. Ketanserin and mianserin (10 and 100 nM), 5-HT2 receptor antagonists, were equipotent in blocking the 5-HT-induced IPs accumulation with pKB values of 8.46 and 8.21, respectively. In contrast, the dose-response curves of 5-HT-induced IPs accumulation were not shifted until the concentrations of NAN-190 and metoclopramide (5-HT1A and 5-HT3 receptor antagonists, respectively) were increased up to 10 microM. 3. Pretreatment of TSMCs with pertussis toxin or cholera toxin did not inhibit the 5-HT-induced IPs accumulation, but partially inhibited the AlF(4-)-induced IPs response. 4. Stimulation of IPs accumulation by 5-HT required the presence of external Ca2+ and was blocked by EGTA. The addition of Ca2+ (3-620 nM) to digitonin-permeabilized TSMCs directly stimulated IPs accumulation. A further Ca(2+)-dependent increase in IPs accumulation was obtained by inclusion of either guanosine 5'-O-(3-thiotriphoshate) (GTP gamma S) or 5-HT. The combination of GTP gamma S and 5-HT elicited an additive effect on IPs accumulation. 5. Treatment with phorbol 12-myristate 13-acetate (PMA, 1 microM, 30 min) abolished the 5-HT-induced IPs accumulation. The concentrations of PMA that gave a half-maximal and maximal inhibition of 5-HT-induced IPs accumulation were 2.2 +/- 0.4 nM and 1 microM, n = 3, respectively. The protein kinase C (PKC) activator, 4 alpha-phorbol 12,13-didecanoate, at 1 microM, did not influence this response. The inhibitory effect of PMA was reversed by staurosporine, a PKC inhibitor, suggesting that the inhibitory effect of PMA is mediated through the activation of PKC. 6. The site of this inhibition was further investigated by examining the effect of PMA on AlF(4-)-induced IPs accumulation in canine TSMCs. AlF(4-)-stimulated IPs accumulation was inhibited by PMA treatment, suggesting that the effect of PMA is distal to the 5-HT receptor. 7. Acetylcholine-induced IPs accumulation was completely inhibited by atropine, but not affected by ketanserin or mianserin, suggesting that 5-HT-induced IPs accumulation is not due to release of acetylcholine.8. These results demonstrate that 5-HT directly stimulates PLC-mediated PI hydrolysis via a pertussis toxin- and cholera toxin-insensitive GTP binding protein in canine TSMCs and that this coupling process is negatively regulated by PKC. 5-HT2 receptors may be predominantly mediating IPs accumulation and presumably IP-induced Ca2+ release may function as the transducing mechanism for 5-HT stimulated contraction of tracheal smooth muscle.
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PMID:5-Hydroxytryptamine receptor-mediated phosphoinositide hydrolysis in canine cultured tracheal smooth muscle cells. 801 56

The effects of cholera toxin and heat stable Escherichia coli (E. coli) enterotoxin on intestinal fluid secretion are commonly considered to be mediated by cyclic nucleotides. It was demonstrated recently, by using the 5-hydroxytryptamine (5-HT)2 receptor antagonist ketanserin and the 5-HT3 receptor antagonist tropisetron, that 5-HT acts as an important mediator in cholera toxin- and heat stable E. coli enterotoxin-induced fluid secretion. In the present investigation ketanserin and tropisetron were compared with the newer 5-HT3 receptor antagonists ondansetron and granisetron versus 5-HT-, cholera toxin- and heat stable E. coli enterotoxin-induced fluid secretion in the rat jejunum in vivo. Both ondansetron and granisetron dose-dependently inhibited 5-HT- and enterotoxin-induced fluid secretion. Ketanserin blocked 5-HT-induced fluid secretion, but only diminished enterotoxin-induced effects even at higher doses. Tropisetron inhibited 5-HT- and cholera toxin-induced effects at high dose but only diminished heat stable E. coli enterotoxin-induced effects. We conclude that 5-HT3 receptors, located on enterochromaffin cells and nervous structures, are more important in mediating fluid secretion than 5-HT2 receptors, located on the epithelial cells.
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PMID:Inhibition of 5-hydroxytryptamine- and enterotoxin-induced fluid secretion by 5-HT receptor antagonists in the rat jejunum. 822 62

We examined the role of 5-hydroxytryptamine (5-HT) in cholera toxin (CT)-induced mucin secretion in the proximal and distal regions of the rat small intestine. Neither the 5-HT2 receptor antagonist ketanserin nor the cyclooxygenase inhibitor indomethacin was capable of inhibiting choleraic mucin secretion. However, in the presence of the mixed 5-HT3/4 receptor antagonist tropisetron at doses that block both receptor subtypes, the secretory response was reduced to baseline levels in the proximal and distal small intestine. The selective 5-HT3 receptor antagonist ondansetron had no significant effect. These findings suggest that choleraic mucin secretion is mediated primarily through the activation of a 5-HT4-like receptor. Mucin secretion in response to the exogenous application of 5-HT occurs via two pathways: one is mediated by a 5-HT4-like receptor and is capsaicin sensitive but tetrodotoxin (TTX) insensitive, and one lacks the capsaicin-sensitive 5-HT4-mediated response but is TTX sensitive. Both converge on a common pathway that is cholinergic. No significant differences were observed between proximal and distal intestinal segments.
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PMID:Role of 5-HT in cholera toxin-induced mucin secretion in the rat small intestine. 876 8


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