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

5-HT3 receptors may be present on primary afferent neurons containing substance P (SP), neurokinin A (NKA) or calcitonin gene-related peptide (CGRP). We investigated the release of SP-, NKA- and CGRP-immunoreactivities (IR) from rat spinal cord slices. Thirty mM potassium chloride caused an increased outflow of all three peptides, i.e. 140-190% of spontaneous release. This release was slightly enhanced in the presence of 3 x 10(-5) M 5-hydroxytryptamine (5-HT). In contrast, a significant inhibition of potassium-evoked, but not of basal NKA-IR and CGRP-IR release was observed when 10(-7) M BRL 43694 or ICS 205-930, two specific 5-HT3 receptor antagonists, were superfused together with 5-HT. In conclusion, 5-HT may facilitate the evoked release of peptides from central terminals of primary sensory neurons via 5-HT3 receptors.
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PMID:5-HT3 receptor antagonists inhibit sensory neuropeptide release from the rat spinal cord. 171 37

1. Intracellular recordings were made from neurones in the nucleus accumbens in slices from the rat brain maintained in vitro. 2. 5-Hydroxytryptamine (5-HT.1-100 microM) depolarized 170 of 203 (84%) neurones and caused them to discharge action potentials. The depolarization was associated with an increase in the input resistance, and was reversed in polarity by conditioning hyperpolarization; this reversal potential was linearly related to the logarithm of the extracellular potassium concentration. 3. Application of 5-HT to neurones voltage-clamped near their resting potential (typically about -80 mV) caused an inward current and a decrease in the slope conductance. The current caused by 5-HT reversed polarity at the potassium equilibrium potential. Analysis with an equivalent circuit model of the neurone at steady state indicated that 5-HT selectively reduced the inward rectifier potassium conductance. 4. The depolarization caused by 5-HT persisted in tetrodotoxin (1 microM). It was reduced but not abolished by a solution that contained lower levels of calcium (0.24 instead of 2.4 mM), higher levels of magnesium (5 instead of 1.2 mM), and cobalt (2 mM). 5. The depolarization caused by 5-HT was competitively antagonized by the 5-HT2 antagonists ketanserin and mianserin with dissociation equilibrium constants of 3 and 45 nM respectively: spiperone (300 nM) also blocked the action of 5-HT. The depolarization was not mimicked or blocked by a number of other agonists and antagonists selective for the 5-HT1 and 5-HT3 receptor types.
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PMID:5-Hydroxytryptamine acts at 5-HT2 receptors to decrease potassium conductance in rat nucleus accumbens neurones. 262 87

The present study has been performed to test for the influence of serotonin on the potential difference across the cell membrane (PD) of Madin-Darby canine kidney (MDCK)-cells. Under control conditions PD averages -48.6 +/- 0.6 mV (n = 98). Increasing extracellular potassium concentration from 5.4 to 10 and 20 mmol/l depolarizes the cell membrane by +6.3 +/- 0.6 mV (n = 6) and +14.1 +/- 1.0 mV (n = 12), respectively. The cell membrane is transiently hyperpolarized to -67.8 +/- 0.8 mV (n = 63) by 1 mumol/l serotonin. In the presence of serotonin, increasing extracellular potassium concentration from 5.4 to 20 mmol/l depolarizes the cell membrane by +26.4 +/- 1.0 mV (n = 11). 1 mmol/l barium depolarizes the cell membrane by +15.7 +/- 1.3 mV (n = 17) and abolishes the effect of step increases of extracellular potassium concentration from 5.4 to 10 mmol/l. In the presence of barium, serotonin leads to a transient hyperpolarization by -26.3 +/- 1.0 mV (n = 16). During this transient hyperpolarization, the cell membrane is sensitive to extracellular potassium concentration despite the continued presence of barium. 10 mumol/l methysergide hyperpolarize the cell membrane by -7.2 +/- 2.0 mV (n = 6). In the presence of 10 mumol/l methysergide, the effect of serotonin is virtually abolished (+0.4 +/- 0.9 mV, n = 6). 1 mumol/l ketanserin, a 5-HT2 receptor blocking agent, ICS 205-930, a 5-HT3 receptor blocking agent, and phentolamine, an unspecific alpha-receptor blocking agent, do not significantly modify the effect of serotonin. In the nominal absence of extracellular calcium, the effect of serotonin is markedly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of serotonin on electrical properties of Madin-Darby canine kidney cells. 289 69

Mouse neuroblastoma cells of the clone N1E-115 express a variety of ion channels and receptors, including a number that is also involved in neurotransmission. Effects of Pb2+ on several of these ion channels have been investigated under experimental conditions that allow electrophysiological recording of membrane current carried by distinct types of ion channels. In whole-cell voltage clamp experiments voltage-dependent calcium channels are blocked by Pb2+ at micromolar concentrations, while voltage-dependent sodium channels are not affected by Pb2+. The neuronal type nicotinic acetylcholine (ACh) receptor-ion channel complex is sensitive to low concentrations of Pb2+. At 1 nM-3 microM, Pb2+ reduces the peak amplitude of the ACh-induced inward current to 74%-10% of the control value in a concentration-dependent manner. However, at Pb2+ concentration between 10 and 100 microM this blocking effect is reduced and kinetics of decay of the ACh-induced inward current are slowed. The effects of Pb2+ on the nicotinic receptor-mediated inward current amplitude can be described by the sum of two sigmoidal concentration-effect curves with an IC50 value of 19 nM and an EC50 of 21 microM. The serotonin 5-HT3 receptor-ion channel complex is less sensitive to Pb2+. The serotonin-induced inward current is blocked by Pb2+ with an IC50 value of 49 microM. In single channel patch clamp experiments internal Pb2+ causes activation of calcium-activated potassium channels in N1E-115 cells. The two types of calcium-activated potassium channels show differential sensitivity: the low conductance (SK) channel is more sensitive to Pb2+ than the high conductance (BK) channel. At micromolar concentrations Pb2+ also induces an ion current mediated by metal ion-activated ion channels. Opening of these channels, which have a single channel conductance of 24 pS and a reversal potential of 0 mV, depends on Pb2+ concentration. These effects of Pb2+ support the hypothesis that Pb2+ affects synaptic transmission by blocking presynaptic voltage-dependent calcium channels. On the other hand, effects on other sensitive target sites, the neuronal nicotinic ACh receptor in particular, clearly indicate that other targets may be involved in the toxic effects of Pb2+ on the nervous system.
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PMID:Differential neurotoxicological effects of lead on voltage-dependent and receptor-operated ion channels. 750 28

1. Intracellular recordings were made from submucosal neurones and single-electrode voltage-clamp methods were used to record membrane currents. The actions of substance P (SP), 5-hydroxytryptamine (5-HT), muscarine, vasoactive intestinal polypeptide (VIP), forskolin and nerve stimulation were studied. 2. Substance P, 5-HT (in the presence of 5-HT3 receptor antagonists), muscarine, VIP, forskolin and slow excitatory synaptic transmission all produced identical responses: an inward current associated with a membrane conductance decrease at the resting potential. The actions of any one occluded the actions of any other and all responses were pertussis-toxin insensitive. 3. These agonists produced a voltage-independent decrease in a 'leak' potassium conductance between -40 and -120 mV in 14% of neurones. 4. These agonists decreased a voltage-dependent, calcium-activated potassium conductance between -40 and -80 mV in all other (86%) neurones. The agonists still evoked an inward current without apparent conductance change at potentials between -90 and -130 mV. 5. In a low calcium solution containing cobalt or cadmium, the agonists produced an inward current associated with a conductance increase from -40 to -120 mV. Ion replacement studies indicated this current was due to an increase in a cation-selective (mainly sodium) conductance. 6. The agonists also reduced the inwardly rectifying potassium current that is activated by somatostatin and alpha 2-adrenoceptor agonists in these neurones. The agonists did not alter the inwardly rectifying potassium current that is present in these neurones in the absence of somatostatin or alpha 2-agonists. 7. Thus, SP, 5-HT, muscarine, VIP and the release of slow excitatory transmitters all appear to act through a common intracellular transduction pathway, an increase in adenylate cyclase. This results in an activation of a sodium-selective cation current and an inhibition of three distinct potassium conductances: the background potassium conductance, the calcium-activated potassium conductance and the inwardly rectifying potassium conductance activated by somatostatin and alpha 2-adrenoceptor agonists.
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PMID:Common ionic mechanisms of excitation by substance P and other transmitters in guinea-pig submucosal neurones. 768 94

There was a significant increase in potassium-stimulated release of 3H-[5-HT] from hippocampal slices taken from rats withdrawn from chronic ethanol treatment, compared with control-treated rats. The anxiogenic behaviour observed 12 h after ethanol withdrawal was inhibited by the 5-HT1A partial agonist, buspirone (200 micrograms/kg s.c.), indicating that the increased 5-HT release might underlie the anxiogenic response. The ex-ethanol treated rats showed impaired habituation of motor activity in the holeboard and a reduced exploratory response. The latter, but not the former, were reversed by the 5-HT3 receptor antagonist, ondansetron (0.01 microgram/kg i.p.). Ondansetron was without effect on working memory errors, but significantly increased the number of reference memory errors made by the ex-ethanol group. It also had a significantly anxiogenic effect in this group. These results suggest that the chronic ethanol treatment changes the 5-HT system and has long-lasting effects on the function of 5-HT3 receptors.
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PMID:The role of 5-HT in the anxiogenic effects of acute ethanol withdrawal and in the long-lasting cognitive deficits. 774 45

The functional modulation of norepinephrine (NE) release by serotonergic receptors in the hippocampus of freely moving rats was studied by use of in vivo microdialysis. To stimulate NE release from the nerve terminals, a high concentration of potassium (K+, 120 mM) was added through the perfusion system. The K(+)-evoked NE release was inhibited in a concentration-dependent manner when serotonin (5-HT, 0.01-10 microM) was coperfused with K+. A selective 5-HT3 receptor agonist, 2-methyl-5-HT, mimicked the 5-HT response at a concentration of 0.01 to 10 microM. The 5-HT-induced (1 microM) inhibition of NE release was blocked by pretreatment with ondansetron (1 and 10 microM), a 5-HT3 receptor antagonist. On the other hand, K(+)-evoked NE release was also reduced by coperfusion with the 5-HT reuptake inhibitor, fluoxetine (10 microM), which caused increases in the dialysate 5-HT concentration. The fluoxetine-induced (10 microM) decreases in the K(+)-evoked NE release were prevented by serotonergic denervation caused by pretreatment with 5,7-dihydroxytryptamine (200 micrograms/rat i.c.v.). These results indicate that the inhibition on NE release by fluoxetine was due to increased synaptic concentrations of endogenous 5-HT. The fluoxetine-induced inhibitory effect was furthermore abolished by pretreatment with ondansetron (1 and 10 microM). These findings indicate the possibility that both exogenous and endogenous 5-HT inhibit NE release occurs from the rat hippocampus by 5-HT3 receptors. Thus, the present study suggests that the functional modulation of NE release by 5-HT3 receptors exists in vivo.
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PMID:Modulation of norepinephrine release by serotonergic receptors in the rat hippocampus as measured by in vivo microdialysis. 789 14

Studies were done to characterize the chronic toxicity, metabolism, and pharmacokinetics of a 5-HT3 receptor antagonist in Fischer 344 rats. Animal were given daily gavage doses of 10, 30, or 90 (females only were increased from 90 to 120 mg/kg for months 7-12) mg/kg of zatosetron for 1 year. Treatment-related histologic changes occurred primarily in the liver and kidney of rats given 30 or 90/120 mg/kg and consisted of hepatocellular fatty change (males only), hepatic granuloma formation, and histiocytosis (females only), and renal pigment deposition (both sexes), lesions not previously described in animals treated with 5-HT3 receptor antagonists. Decreased erythrocyte parameters, increased total leukocyte, lymphocyte, and neutrophil counts, and increased serum alkaline phosphatase, gamma glutamyltransferase, alanine transaminase, and liver weights in females were most likely related to the chronic inflammatory process in the liver. Increased alanine transaminase and transiently increased alkaline phosphatase with increased liver weights in males were likely related to the hepatocellular fatty change. Increased renal tubular epithelial pigment deposition (lipofuscin and hemosiderin) was observed in males and females in the high-dose group and in females in the middle-dose group. Both had increased kidney weights and increased serum inorganic phosphorus. Females in the high-dose group had increased urine volume, decreased pH, and increased total excretion of sodium, potassium, chloride, and creatinine. These changes may have been a reflection of tubular dysfunction associated with excessive pigment deposition. No toxicologically significant effects occurred in rats treated with 10 mg/kg/day for 1 year. Plasma concentrations of zatosetron and its 3-hydroxy metabolite increased with increasing dose and duration of dosing in both males and females during the first 6 months of dosing. Subsequent values measured at 12 months showed no substantive increases except in males given the highest dose. At comparable doses, consistent sex differences (F > M) in mean 1-hr plasma content of parent compound were evident across dose and time. Zatosetron-induced hepato- and nephrotoxicity seems to be peculiar to the rat and is observed only at very high doses relative to the proposed human clinical dose.
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PMID:Chronic toxicity, metabolism, and pharmacokinetics of the 5-HT3 receptor antagonist zatosetron (LY277359) in Fischer 344 rats. 805 97

The objective of this study was to explore the role of 5-HT3 receptors in modulating potassium (K+)-evoked release of [3H]-acetylcholine ([3H]-ACh) from superfused slices of rat entorhinal cortex previously loaded with [3H]-choline. Rat entorhinal cortices were cross-chopped into 300 microns slices, superfused with oxygenated Krebs buffer containing 2.5 mmol/l Ca2+ and stimulated with two consecutive exposures of 20 mmol/l K+ for 4 min (S1 and S2, respectively). Compounds were added 20 min before S2 stimulation and remained in the superfusion buffer for the duration of the experiment. The S2/S1 ratio was then calculated. Stimulated release of [3H]-ACh was dependent on extracellular Ca2+ and K+ concentration. In Sprague Dawley rats, 2-methyl-5-HT (10(-9)-10(-6) mol/l), in the presence of 1 mumol/l ritanserin or 1 mumol/l ondansetron, had no influence on K(+)-evoked release of [3H]-ACh. In slices prepared from Hooded Lister rats, 2 mumol/l 5-HT but not 2-Me-5-HT significantly (P < 0.05) inhibited K(+)-evoked [3H]-ACh release only 17% in the presence of 1 mumol/l ritanserin. However, 2 mumol/l 2-Me-5-HT plus 1 nmol/l ondansetron had no effect. High performance liquid chromatography coupled to electrochemical detection (HPLC-ECD) was used to monitor endogenous release of ACh in the above conditions to confirm data from the radiolabelled experiments. No significant inhibition or increase in K(+)-evoked ACh release was observed with either 5-HT3 receptor agonists or antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-HT3 receptor ligands lack modulatory influence on acetylcholine release in rat entorhinal cortex. 847 44

In this study we have investigated the acute and chronic effects of cisplatin on whole cell currents in cultured dorsal root ganglion neurones. Consistent with effects on action potentials measured under current clamp, acute (5 min) application of cisplatin (5 microM) attenuated voltage-activated potassium, and mixed cation currents by approximately 50% in both cases. Chronic treatment (5-7 days) of cultured neurones with 5 microM cisplatin also resulted in greatly reduced voltage-activated potassium currents (by 50%) and calcium currents (by 60%) compared to events recorded from neurones not treated with cisplatin. In contrast, the amplitude of inward cation current activated by hyperpolarization was doubled by 5-12 days treatment with cisplatin. Studies on action potential after-depolarizations and calcium-activated chloride currents suggest that cisplatin disturbs calcium homeostatic mechanisms. These observations may account for anode break spike excitation and the low efficiency with which cells buffer intracellular calcium following cisplatin treatment. Dexamethasone has been found to enhance the anti-emetic effects of 5-HT3 receptor antagonists in patients treated with cisplatin. For this reason the actions of dexamethasone were studied in combination with cisplatin treatment. Although acute application of dexamethasone (1-10 microM) produced transient depolarizations and bursts of action potentials, after 5 minutes application it had no effect on membrane potential, input resistance, or the properties of action potentials evoked by depolarizing current commands.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An electrophysiological investigation of the effects of cisplatin and the protective actions of dexamethasone on cultured dorsal root ganglion neurones from neonatal rats. 858 39


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