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

1. The effect of micromolar concentrations of divalent metal cations on ion current activated by 5-hydroxytryptamine (5-HT) was investigated in NCB-20 neuroblastoma cells by the use of the whole-cell, patch-clamp technique. 2. Ion current activated by 5-HT in these cells was mimicked by 5-HT3 receptor agonists, blocked by nanomolar concentrations of selective 5-HT3 receptor antagonists and reversed polarity at approximately 0 mV. These properties indicate that this current is carried primarily if not exclusively by the nonspecific cation channel activated by the 5-HT3 receptor. 3. The Group IIb metal cations Cd2+ and Zn2+ and the Group Ib cation Cu2+ inhibited 5-HT-activated current with inhibition increasing in a concentration-dependent manner over micromolar concentrations of the ions. The order of potency of the ions for inhibiting 5-HT-activated current was Zn2+ (IC50 = 20 microM) greater than or equal to Cu2+ (IC50 = 25 microM) greater than Cd2+ (IC50 = 75 microM) at -50 mV. The other divalent metal cations tested (Ba2+, Co2+, Mg2+, Mn2+, and Ni2+) produced little or no inhibition of 5-HT-activated current at concentrations up to 200 microM. 4. Inhibition of 5-HT-activated current by Cd2+ and Zn2+ was dependent on membrane potential with the Kd increasing e-fold per 72 and 52 mV, respectively. Inhibition by Cu2+ was much less voltage dependent with the Kd increasing e-fold per 233 mV. 5. Inhibition by all three cations decreased with increasing concentration of agonist over a range of 5-HT concentrations from 1 to 10 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of 5-HT3 receptor-mediated ion current by divalent metal cations in NCB-20 neuroblastoma cells. 172 46

Ionic currents induced by 5-hydroxytryptamine (5-HT) in cultured neuroblastoma N18 cells were studied using whole-cell voltage clamp. The response was blocked by 1-10 nM 5-HT3 receptor-specific antagonists MDL 7222 or ICS 205-930, but not by 1 microM 5-HT1/5-HT2 receptor antagonist spiperone or 5-HT2 receptor-specific antagonist ketanserin. These 5-HT3 receptors seem to be ligand-gated channels because the response (a) did not require internal ATP or GTP, (b) persisted with long internal dialysis of CsF (90 mM), A1F4- (100 microM), or GTP gamma S (100 microM), and (c) with ionophoretic delivery of 5-HT developed with a delay of less than 10 ms and rose to a peak in 34-130 ms. Fluctuation analysis yielded an apparent single-channel conductance of 593 fS. The relative permeabilities of the channel for a variety of ions were determined from reversal potentials. The channel was only weakly selective among small cations, with permeability ratios PX/PNa of 1.22, 1.10, 1.01, 1.00, and 0.99 for Cs+, K+, Li+, Na+, and Rb+, and 1.12, 0.79, and 0.73 for Ca2+, Ba2+, and Mg2+ (when studied in mixtures of 20 mM divalent ions and 120 mM N-methyl-D-glucamine). Apparent permeability ratios for the divalent ions decreased as the concentration of divalent ions was increased. Small monovalent organic cations were highly permeant. Large organic cations such as Tris and glucosamine were measurably permeant with permeability ratios of 0.20 and 0.08, and N-methyl-D-glucamine was almost impermeant. Small anions, NO3-, Cl-, and F-, were slightly permeant with permeability ratios of 0.08, 0.04, and 0.03. The results indicate that the open 5-HT3 receptor channel has an effective minimum circular pore size of 7.6 A and that ionic interactions in the channel may involve negative charges near the pore mouth.
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PMID:Ion permeation through 5-hydroxytryptamine-gated channels in neuroblastoma N18 cells. 228 32

The influence of extracellular calcium and magnesium ion concentrations upon 5-HT3 receptor-gated membrane currents in murine N1E-115 neuroblastoma cells has been studied under voltage-clamp conditions. A decrease in the concentration of either Ca2+ or Mg2+ from their standard values of 1.0 and 2.0 mM respectively augmented both the amplitude and duration of the 5-HT-induced current, whereas elevating the concentration of either divalent cation produced the opposite effect. Such modulation did not involve a change in the reversal potential of the response.
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PMID:Divalent cations modulate 5-HT3 receptor-induced currents in N1E-115 neuroblastoma cells. 246 26

1. The biophysical and pharmacological properties of 5-hydroxytryptamine (5-HT)-evoked currents in rabbit nodose ganglion neurones in culture have been determined by use of the whole-cell and outside-out membrane patch recording modes of the patch-clamp technique. 2. In 49% of cells investigated the bath application of 10(-5) M 5-HT at negative holding potentials elicited an inward current. The whole-cell response to 5-HT reversed in sign (E5-HT) at approximately -2 mV and exhibited inward rectification. 3. The influence of various ion substitutions upon E5-HT established that the 5-HT-evoked current is mainly mediated by a mixed Na+, K+ cation conductance with little or no contribution from Cl- ions. The omission of Ca2+ and Mg2+ from the extracellular solution enhanced the amplitude of the 5-HT-induced current. 4. On isolated outside-out membrane patches, the bath application of 10(-6) M 5-HT induced single channel currents with a chord conductance of approximately 17 pS at -70 mV and an average slope conductance of 19 pS over the range -100 to -40 mV. The 5-HT-induced single channels exhibited modest inward rectification and were reduced in frequency, but not amplitude, by the 5-HT3 receptor antagonist metoclopramide (10(-6) M). 5. The bath application of 5-HT (3 x 10(-7)-3 x 10(-5) M) to whole cells voltage clamped at -60 mV produced dose-dependent inward currents which were mimicked by 2-methyl-5-HT and 1-phenylbiguanide with equipotent molar ratios, relative to 5-HT, of 2.5 and 32 respectively. 6. Whole-cell inward currents produced by the local pressure application of 5-HT (10(-5) M) were unaffected by 10(-6) M methysergide, 10(-6) M ketanserin or 10(-6) M citalopram, but were concentration-dependently antagonized by the selective 5-HT3 receptor antagonists tropisetron (IC50 = 4.6 x 10(-11) M) ondansetron (IC50 = 5.7 x 10(-11) M), and bemesetron (IC50 = 3.3 x 10(-10) M). The response to 5-HT was also blocked by the non-selective antagonists metoclopramide (IC50 = 1.2 x 10(-8) M), cocaine (IC50 = 8.3 x 10(-8) M) and (+)-tubocurarine (IC50 = 1.6 x 10(-7) M).
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PMID:An electrophysiological investigation of the properties of 5-HT3 receptors of rabbit nodose ganglion neurones in culture. 769 55

We have examined the ability of divalent cations to inhibit 3H-GR 65630 binding to 5-HT3 receptor recognition sites in rat brain cortical membranes. Among the divalent metal cations tested, Cd2+, Zn2+ and Cu2+ inhibited the specific 3H-GR 65630 binding activity to 5-HT3 receptors at a concentration of 0.1-1 mM. The other divalent metal cations tested (i.e. Co2+, Ni2+, Ba2+, Ca2+, Mg2+ and Mn2+) produced no inhibition of the specific 3H-GR 65630 binding. Cd2+, Zn2+ and Cu2+ did not change the Bmax value of the binding activity, but significantly increased the Kd value. It was suggested that these cations inhibited the binding activity by reducing affinity of the 5-HT3 receptor for the antagonist, resulting in apparent inhibition of the binding activity. As to the binding association rate, Cd2+, Cu2+ and Zn2+ were found to have an inhibitory effect. The binding dissociation rate, however, was shown to be decreased by Cu2+ but not by Cd2+ and Zn2+. Furthermore, the Zn(2+)-induced inhibition of 3H-GR 65630 binding was suggested to be antagonized by both concanavalin A and wheatgerm agglutinin. The Cu(2+)-induced inhibition, however, was not influenced by these lectins, indicating that Cu2+ has a different lectin sensitivity for its inhibitory effect. The different mechanism of action between Cu2+ and Zn2+ was suggested in their inhibitory effect on the specific 3H-GR 65630 binding activity.
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PMID:Differential effects of divalent cations on specific 3H-GR 65630 binding to 5-HT3 receptors in rat cortical membranes. 802 34

Confocal microscopy was used to assess internal calcium level changes in response to presynaptic receptor activation in individual, isolated nerve terminals (synaptosomes) from rat corpus striatum, focusing, in particular, on the serotonin 5-HT3 receptor, a ligand-gated ion channel. The 5-HT3 receptor agonist-induced calcium level changes in individual synaptosomes were compared with responses evoked by K+ depolarization. Using the fluorescent dye fluo-3 to measure relative changes in internal free Ca2+ concentration ([Ca2+]i), K+-induced depolarization resulted in variable but rapid increases in apparent [Ca2+]i among the individual terminals, with some synaptosomes displaying large transient [Ca2+]i peaks of varying size (two- to 12-fold over basal levels) followed by an apparent plateau phase, whereas others displayed only a rise to a sustained plateau level of [Ca2+]i (two- to 2.5-fold over basal levels). Agonist activation of 5-HT3 receptors induced slow increases in [Ca2+]i (rise time, 15-20 s) in a subset (approximately 5%) of corpus striatal synaptosomes, with the increases (averaging 2.2-fold over basal) being dependent on Ca2+ entry and inhibited by millimolar external Mg2+. We conclude that significant increases in brain nerve terminal Ca2+, rivaling that found in response to excitation by depolarization but having distinct kinetic properties, can therefore result from the activation of presynaptic ligand-gated ion channels.
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PMID:Direct observation of serotonin 5-HT3 receptor-induced increases in calcium levels in individual brain nerve terminals. 876 83

Pancreatic ganglia contain 5-hydroxytryptamine (5-HT)-immunoreactive axons, some of which are extensions of myenteric neurons located in the pyloric antrum and proximal duodenum. The present study investigated the effect of 5-HT on the membrane potential of cat pancreatic ganglion neurons by means of intracellular recordings in vitro. Pressure application of 5-HT evoked a fast depolarization in 29 of 147 neurons and a slow depolarization in 89 of 147 neurons. A biphasic response was observed in 10 of 108 neurons. The 5-HT-induced slow depolarizing response was not altered in a low Ca2+ (0.1 mM), high Mg2+ (15 mM) solution nor by hexamethonium (10(-4) M) or atropine (10(-6) M). The fast depolarizing response was associated with a decrease of membrane input resistance (-17.2%). The slow depolarizing response was associated with either a decrease (-19.6%) in 24, an increase (+25.0%) in 20, or without a detectable change of membrane input resistance in 10 out of 54 neurons tested. Conditioning hyperpolarization increased the amplitude of both fast and slow depolarizing responses. A low Na+ (68.5 mM) solution and a high K+ (23.5 mM) solution significantly reduced the amplitude of the slow depolarizing response. A low Cl- (9.6 mM) solution had no significant effect on the slow depolarization. The 5-HT3 receptor antagonist MDL 72222 (Bemesetron) blocked the 5-HT-evoked fast depolarizing response. BRL 24924 (Renzapride) and 5 HT-DP, antagonists for the putative 5-HT1P receptor, blocked the slow depolarizing response. The 5-HT3 receptor agonist 2-methyl-5-HT evoked a fast depolarizing response and MCPP, an agonist for the putative 5-HT1P receptor, evoked a slow depolarizing response. Spiperone (a 5-HT1A receptor antagonist) and mianserin (a 5-HT2 receptor antagonist) had no effect on either depolarizing response to 5-HT. The results show that pancreatic ganglion neurons responded to 5-HT with fast and slow depolarizing responses. The data suggest that these responses were mediated by the 5-HT3 receptor and the putative 5-HT1P receptor, respectively.
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PMID:5-Hydroxytryptamine depolarizes neurons of cat pancreatic ganglia. 886 89

The effects of changes in external K+, Ca2+, and Mg2+ concentrations on 5-HT2- and 5-HT3 receptor-mediated depolarizations of the resting membrane potential in rat dorsal root ganglion (DRG) cells was studied. In cells exhibiting a 5-HT2-mediated response, 5-HT and alpha-methyl 5-HT depolarized the resting membrane potential (RMP) and increased the slope of the current-voltage (I/V) relationship. The equilibrium potential (Er) for the depolarization was linearly related to the logarithm of the [K+]o, indicating the depolarization resulted from a decrease in resting K+ conductance. In a subpopulation of large-diameter acutely dissociated DRG neurons recorded from using the whole-cell patch-clamp configuration, 5-HT produced an inward shift in the current required to hold cells at -60 mV. This inward shift in holding current was associated with a reduction in membrane conductance and reversed near Ek. This data suggests that the 5-HT2 receptor-mediated depolarization and increase in R(in) seen in intact DRG preparation is produced by blockade of an outward K+ leak current. Increases in [K+]o reduced the increase in R(in) and depolarization induced by 5-HT with 50% inhibition of the depolarization occurring at 8.3 mM of [K+]o. Half-normal Ca2+ (1.2 mM) produced a downward shift of the 5-HT concentration-response curve, reducing the maximal response by 40%, with minimal effect on the half-maximal response. Mg2+ ions did not affect this 5-HT response. In cells exhibiting a 5-HT3 receptor response, 5-HT and 2-methyl-5-HT produced depolarization with decreased R(in). The Er for this depolarizing response (-30.2 +/- 1.8 mV) became less negative (-11.5 mV) in 10 mM [K+]o with minimal effect on the amplitude of the depolarization. In Na(+)-free superfusate, the 5-HT-induced depolarization was converted to hyperpolarization. This indicated the 5-HT3 response increased a mixed Na+/K+ conductance. Elevated Ca2+ or Mg2+ markedly reduced the 5-HT3 response. Incubation with 3.5 mM Ca2+ shifted the 5-HT concentration-response curve downward and to the right, decreasing the maximal response by 49% and increasing the EC50 by 10-fold. Elevated Mg2+ produced similar effects. In cells where both 5-HT2- and 5-HT3-mediated responses could be demonstrated, the elevation of K+ or the reduction of Ca2+ converted a 5-HT2 response to a 5-HT3 response. The above data suggest that elevation of [K+]o or reduction of [Ca2+]o produced by rapid firing rates of sensory neurons will favor the expression of 5-HT3 responses over 5-HT2 responses.
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PMID:Cationic modulation of 5-HT2 and 5-HT3 receptors in rat sensory neurons: the role of K+, Ca2+ and Mg2+. 931 2

1. A human recombinant homo-oligomeric 5-HT3 receptor (h5-HT3A) expressed in a human embryonic kidney cell line (HEK 293) was characterized using the whole-cell recording configuration of the patch clamp technique. 2. 5-HT evoked transient inward currents (EC50 = 3.4 microM; Hill coefficient = 1.8) that were blocked by the 5-HT3 receptor antagonist ondansetron (IC50 = 103 pM) and by the non-selective agents metoclopramide (IC50 = 69 nM), cocaine (IC50 = 459 nM) and (+)-tubocurarine (IC50 = 2.8 microM). 3. 5-HT-induced currents rectified inwardly and reversed in sign (E5-HT) at a potential of -2.2 mV. N-Methyl-D-glucamine was finitely permeant. Permeability ratios PNa/PCs and PNMDG/PCs were 0.90 and 0.083, respectively. 4. Permeability towards divalent cations was assessed from measurements of E5-HT in media where Ca2+ and Mg2+ replaced Na+. PCa/PCs and PMg/PCs were calculated to be 1.00 and 0.61, respectively. 5. Single channel chord conductance (gamma) estimated from fluctuation analysis of macroscopic currents increased with membrane hyperpolarization from 243 fS at -40 mV to 742 fS at -100 mV. 6. Reducing [Ca2+]o from 2 to 0.1 mM caused an increase in the whole-cell current evoked by 5-HT. A concomitant reduction in [Mg2+]o produced further potentiation. Fluctuation analysis indicates that a voltage-independent augmentation of gamma contributes to this phenomenon. 7. The data indicate that homo-oligomeric receptors composed of h5-HT3A subunits form inwardly rectifying cation-selective ion channels of low conductance that are permeable to Ca2+ and Mg2+.
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PMID:Ion permeation and conduction in a human recombinant 5-HT3 receptor subunit (h5-HT3A). 950 27

1. Recordings were made from a total of sixty-four vagal preganglionic neurones in the dorsal vagal motor nucleus (DVMN) of pentobarbitone sodium anaesthetized rats. The effects of ionophoretic administration of Mg2+ and Cd2+, inhibitors of neurotransmitter release, and the selective NMDA and non-NMDA receptor antagonists (+/-)-2-amino-5-phosphono-pentanoic acid (AP5) and 6,7-dinitroquinoxaline-2,3-dione (DNQX) on the excitatory actions of the 5-HT3 receptor agonist 1-phenylbiguanide (PBG) were studied. 2. In extracellular recording experiments, PBG (0-40 nA) increased the firing rate of thirty-five of the thirty-nine neurones tested. The PBG-evoked excitation was attenuated by application of Mg2+ (1-10 nA) in sixteen of seventeen neurones or Cd2+ (2-10 nA) in seven of eight neurones tested. At these low ejection currents neither Mg2+ nor Cd2+ altered baseline firing rates and Mg2+ had no effect on the excitations evoked by DL-homocysteic acid (n = 4), NMDA (n = 4) or (AMPA; n = 2). 3. Ionophoresis of AP5 (2-10 nA), at currents which selectively inhibited NMDA-evoked excitations, attenuated PBG-evoked excitations in all eight neurones tested. DNQX (5-20 nA), at currents which selectively inhibited AMPA-evoked excitations, also attenuated PBG-evoked excitations (n = 3). 4. Intracellular activity was recorded in nine DVMN neurones. In six neurones ionophoretic application of PBG (10-200 nA) depolarized the membrane and increased firing rate whilst in the other three neurones, PBG had no effect on membrane potential though it increased synaptic noise (n = 3) and firing rate (n = 2). In all six neurones tested, ionophoresis of Mg2+ (10-120 nA) attenuated the PBG-evoked increases in synaptic noise and firing rate. 5. In conclusion, the data are consistent with the hypothesis that 5-HT3 receptor agonists activate DVMN neurones partly by acting on receptors located at sites presynaptic to the neurones. Activation of these receptors appears to facilitate release of glutamate, which, in turn, acts on postsynaptic NMDA and non-NMDA receptors to activate the neurones.
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PMID:Presynaptic 5-HT3 receptors evoke an excitatory response in dorsal vagal preganglionic neurones in anaesthetized rats. 959 91


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