Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several human Mendelian diseases, including the long-QT syndrome, malignant hyperthermia, and episodic ataxia/myokymia syndrome, have recently been demonstrated to be due to mutations in ion channel genes. Systematic mapping of ion channel genes may therefore reveal candidates for other heritable disorders. In this study, the GenBank and dbEST databases were used to identify members of several ion channel families (voltage-gated calcium and sodium, cardiac chloride, and all classes of potassium channels). Genes and ESTs without prior map localization were identified based on GDB and OWL database information and 15 genes and ESTs were selected for mapping. Of these 15, only the serotonin receptor 5HT3R had been previously mapped to a chromosome. A somatic cell hybrid panel (SCH) was screened with an STS from each gene and, if necessary the results verified by a second SCH panel. For three ESTs, rodent derived PCR products of the same size as the human STS precluded SCH mapping. For these three, human P1 clones were isolated and the genomic location was determined by metaphase FISH. These genes and ESTs can now be further evaluated as candidate genes for inherited cardiac, neuromuscular and psychiatric disorders mapped to these chromosomes. Furthermore, the ESTs developed in this study can be used to isolate genomic clones, enabling the determination of each transcript's genomic structure and physical map location. This approach may also be applicable to other gene families and may aid in the identification of candidate genes for groups of related heritable disorders.
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PMID:Chromosomal localization of 15 ion channel genes. 903 51

The present study was conducted on peripheral blood lympho-cytes of rainbow trout (Oncorhynchus mykiss) to assess the role of 5-hydroxytryptamine (5-HT; 'serotonin') in calcium signalling. 5-HT-induced increases in intracellular free calcium concentrations, [Ca2+]i, and its action was mediated by 5-HT receptor subtype 3 (5-HT3), but not by 5-HT receptor subtype 1A (5-HT1A) or subtype 2 (5-HT2) in these cells. In Ca2+-containing medium (1 mM CaCl2), 5-HT and 2-methyl-5-HT (5-HT3 receptor agonist) induced increases in [Ca2+]i, whereas in Ca2+-free medium (0 Ca2+, 1 mM EGTA), these two agents failed to evoke increases in [Ca2+]i in these cells, demonstrating that 5-HT mobilizes Ca2+ from the extracellular environment. Furthermore, 5-HT-induced increases in [Ca2+]i are not contributed to by the intracellular endoplasmic reticulum (ER) pool, as thapsigargin, an agent that recruits Ca2+ from ER stores, had additive effects on 5-HT-induced [Ca2+]i responses in fish peripheral lymphocytes. 5-HT-induced increases in [Ca2+]i were mediated by 5-HT3 receptors via gating the calcium through L-type, but not N-type, calcium channels in trout lymphocytes.
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PMID:5-Hydroxytryptamine-induced calcium-channel gating in rainbow trout (Oncorhynchus mykiss) peripheral blood lymphocytes. 917 90

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

Little is definitively known of the identity or actions of neurotransmitters utilized within mammalian taste buds. Serotonin has been immunocytochemically localized to taste cells of several species but its physiological actions are unknown. Using whole-cell patch clamp recordings on dissociated posterior rat taste cells, data are presented to suggest that exogenously applied serotonin inhibits a calcium-activated potassium current by up to 50%. This current, best visualized at depolarized holding potentials, is both apamin- and charybdotoxin-sensitive. Approximately 60% of the tested taste cells were serotonin sensitive. This inhibition was mimicked by N-(3-trifluoromethylphenyl)piperazine (TFMPP), a general serotonin receptor agonist, by 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, but not by phenylbiguanide, a 5-HT3 receptor agonist. These are the first data to establish a physiological effect of serotonin on mammalian taste cells.
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PMID:Serotonin inhibits calcium-activated K+ current in rat taste receptor cells. 935 53

Slices from rat midbrain containing the raphe nuclei and from hippocampus were prepared, loaded with [3H]5-HT and superfused and the resting and the electrically stimulated [3H]5-HT release was measured. The 5-HT3 receptor agonist 2-methyl-5-HT (1 to 10 micromol/l) increased the resting tritium outflow in superfused raphe nuclei slices, EC50 5.3 micromol/l. The 2-methyl-5-HT-induced increase of tritium outflow was an external Ca2+-independent process and was not altered by reserpine pretreatment but it was reversed by addition of the 5-HT uptake inhibitor fluoxetine (1 micromol/l). The 5-HT3 receptor antagonists ondansetron and GYKI-46 903 (1 micromol/l) did not antagonize the stimulatory effect of 2-methyl-5-HT on resting tritium outflow. 2-Methyl-5-HT in lower concentration increased the electrically induced tritium overflow from raphe nuclei slices (EC50 0.56 micromol/l) and also from hippocampal slices preloaded with [3H]5-HT. These effects were reversed by 1 micromol/l of ondansetron and GYKI-46903. The 5-HT3 receptor antagonists (1 micromol/l) were without effects on depolarization-evoked [3H]5-HT release at 2 Hz stimulation, when 10 Hz stimulation was used, ondansetron and GYKI-46 903 reduced the tritium overflow from raphe nuclei slices. These data indicate that 5-HT3 receptors positively alter depolarization-induced somatodendritic 5-HT release in the raphe nuclei. They also show that 2-methyl-5-HT is able to evoke 5-HT release not only from vesicles but also from cytoplasmic stores via a transporter-dependent exchange process.
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PMID:Feedback stimulation of somatodendritic serotonin release: a 5-HT3 receptor-mediated effect in the raphe nuclei of the rat. 944 41

A complete understanding of how excitatory ligand-gated ion channels regulate intracellular Ca2+ in nerve cells remains to be elucidated. Laser-scanning confocal microscopy was used here to measure Ca2+ changes in the neuroblastoma x glioma hybrid cell line NG108-15, employed as a model nerve cell line, upon activation by the 5-HT3 receptor, a serotonin-activated ligand-gated ion channel. Addition of the 5-HT3 agonist 1-m-(chlorophenyl)-biguanide (mCPBG) induced increases in [Ca2+]i in both the cytoplasm and the nuclei of the NG108-15 cells. Using high-time resolution line scanning, no delay was evident between the mCPBG-induced rise in cytosolic [Ca2+]i and the rise in nuclear [Ca2+]i. The agonist-induced responses were completely blocked by addition of EGTA to chelate external Ca2+ and by addition of the 5-HT3 receptor antagonist tropisetron or the L-type Ca2+ channel blocker nitrendipine. Caffeine, but not thapsigargin, treatment significantly reduced the mCPBG-induced responses in the nucleus and the cytoplasm, both to the same extent. We conclude that, upon 5-HT3 receptor activation, Ca2+ enters the cells through voltage-gated Ca2+ channels and then triggers the release of Ca2+ from ryanodine-sensitive intracellular stores, greatly amplifying the increases in Ca2+ in the cytoplasm and the nucleus.
Cell Calcium 1997 Nov
PMID:5-HT3 receptors induce rises in cytosolic and nuclear calcium in NG108-15 cells via calcium-induced calcium release. 944 42

The serotonin 5-HT3 receptor, a ligand-gated ion channel, has previously been shown to be present on a subpopulation of brain nerve terminals, where, on activation, the 5-HT3 receptors induce Ca2+ influx. Whereas postsynaptic 5-HT3 receptors induce depolarization, being permeant to Na+ and K+, the basis of presynaptic 5-HT3 receptor-induced calcium influx is unknown. Because the small size of isolated brain nerve terminals (synaptosomes) precludes electrophysiological measurements, confocal microscopic imaging has been used to detect calcium influx into them. Application of 100 nM 1-(m-chlorophenyl)biguanide (mCPBG), a highly specific 5-HT3 receptor agonist, induced increases in internal free Ca2+ concentration ([Ca2+]i) and exocytosis in a subset of corpus striatal synaptosomes. mCPBG-induced increases in [Ca2+]i ranged from 1.3 to 1.6 times over basal values and were inhibited by 10 nM tropisetron, a potent and highly specific 5-HT3 receptor antagonist, but were insensitive to the removal of external free Na+ (substituted with N-methyl-D-glucamine), to prior depolarization induced on addition of 20 mM K+, or to voltage-gated Ca2+ channel blockade by 10 microM Co2+/Cd2+ or by 1 microM omega-conotoxin MVIIC/1 microM oemga-conotoxin GVIA/200 nM agatoxin TK. In contrast, the Ca2+ influx induced by 5-HT3 receptor activation in NG108-15 cells by 1 microM mCPBG was substantially reduced by 10 microM Co2+/Cd2+ and was completely blocked by 1 microM nitrendipine, an L-type Ca2+ channel blocker. We conclude that in contrast to the perikaryal 5-HT3 receptors, presynaptic 5-HT3 receptors appear to be uniquely calcium-permeant.
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PMID:High calcium permeability of serotonin 5-HT3 receptors on presynaptic nerve terminals from rat striatum. 948 30

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

The techniques of intracellular recording and single-electrode voltage-clamp were used to study the effect of serotonin (5-HT) and the selective 5-HT3 receptor agonist SR 57227A on N-methyl-D-aspartic acid (NMDA)-evoked responses in pyramidal cells of the rat medial prefrontal cortex (mPFC) in in vitro brain slice preparations. Bath application of 5-HT or SR 57227A produced a concentration-dependent inhibition of NMDA-induced membrane depolarization, action potentials, and inward current. The depressant action of 5-HT and SR 57227A had a slow onset and showed no signs of receptor desensitization. This action was markedly attenuated or completely blocked by the selective 5-HT3 receptor antagonists granisetron and BRL 46470A, but not other receptor antagonists. In addition to inhibiting NMDA-evoked responses, SR 57227A also depressed significantly pharmacologically isolated, NMDA receptor-mediated, monosynaptic excitatory postsynaptic currents (EPSCs) elicited by electrical stimulation of the forceps minor; this inhibitory action was blocked by BRL 46470A but not other 5-HT receptor antagonists. Perfusion of Ca2+-free or low Ca2+ plus Cd2+ artificial cerebrospinal fluid prevented electrical stimulation-induced EPSCs, but did not affect the inhibitory action of 5-HT and SR 57227A. In conclusion, we demonstrate for the first time that 5-HT and SR 57227A interact with 5-HT3-like receptors to produce a direct inhibitory action on NMDA receptor-mediated response in pyramidal cells of the mPFC.
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PMID:Inhibition of NMDA-receptor mediated response in the rat medial prefrontal cortical pyramidal cells by the 5-HT3 receptor agonist SR 57227A and 5-HT: intracellular studies. 963 96

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays an important regulatory role in developing and adult nervous systems. With the exception of the 5-HT3 receptor, all of the cloned serotonin receptors belong to the G protein-coupled receptor superfamily. Subtypes 5-HT6 and 5-HT7 couple to stimulation of adenylyl cyclases through Gs and display high affinities for antipsychotic and antidepressant drugs. In the brain, mRNA for 5-HT6 is found at high levels in the hippocampus, striatum, and nucleus accumbens. 5-HT7 mRNA is most abundant in the hippocampus, neocortex, and hypothalamus. To better understand how serotonin might control cAMP levels in the brain, we coexpressed 5-HT6 or 5-HT7A receptors with specific isoforms of adenylyl cyclase in HEK 293 cells. The 5-HT6 receptor functioned as a typical Gs-coupled receptor in that it stimulated AC5, a Gs-sensitive adenylyl cyclase, but not AC1 or AC8, calmodulin (CaM)-stimulated adenylyl cyclases that are not activated by Gs-coupled receptors in vivo. Surprisingly, serotonin activation of 5-HT7A stimulated AC1 and AC8 by increasing intracellular Ca2+. 5-HT also increased intracellular Ca2+ in primary neuron cultures. These data define a novel mechanism for the regulation of intracellular cAMP by serotonin.
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PMID:Stimulation of type 1 and type 8 Ca2+/calmodulin-sensitive adenylyl cyclases by the Gs-coupled 5-hydroxytryptamine subtype 5-HT7A receptor. 965 36


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