This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel.
The neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) mediates rapid excitatory responses through ligand-gated channels (5-HT3 receptors). Recombinant expression of the only identified receptor subunit (5-HT3A) yields functional 5-HT3 receptors. However, the conductance of these homomeric receptors (sub-picosiemens) is too small to be resolved directly, and contrasts with a robust channel conductance displayed by neuronal 5-HT3 receptors (9-17 pS). Neuronal 5-HT3 receptors also display a permeability to calcium ions and a current-voltage relationship that differ from those of homomeric receptors. Here we describe a new class of 5-HT3-receptor subunit (5-HT3B). Transcripts of this subunit are co-expressed with the 5-HT3A subunit in the amygdala, caudate and hippocampus. Heteromeric assemblies of 5-HT3A and 5-HT3B subunits display a large single-channel conductance (16 pS), low permeability to calcium ions, and a current-voltage relationship which resembles that of characterized neuronal 5-HT3 channels. The heteromeric receptors also display distinctive pharmacological properties. Surprisingly, the M2 region of the 5-HT3B subunit lacks any of the structural features that are known to promote the conductance of related receptors. In addition to providing a new target for therapeutic agents, the 5-HT3B subunit will be a valuable resource for defining the molecular mechanisms of ion-channel function.
5-hydroxytryptamine type 3 (5-HT3) receptors are cation-selective transmitter-gated ion channels of the Cys-loop superfamily. The single-channel conductance of human recombinant 5-HT3 receptors assembled as homomers of 5-HT3A subunits, or heteromers of 5-HT3A and 5-HT3B subunits, are markedly different, being 0.4 pS (refs 6, 9) and 16 pS (ref. 7), respectively. Paradoxically, the channel-lining M2 domain of the 5-HT3A subunit would be predicted to promote cation conduction, whereas that of the 5-HT3B subunit would not. Here we describe a determinant of single-channel conductance that can explain these observations. By constructing chimaeric 5-HT3A and 5-HT3B subunits we identified a region (the 'HA-stretch') within the large cytoplasmic loop of the receptor that markedly influences channel conductance. Replacement of three arginine residues unique to the HA-stretch of the 5-HT3A subunit by their 5-HT3B subunit counterparts increased single-channel conductance 28-fold. Significantly, ultrastructural studies of the Torpedo nicotinic acetylcholine receptor indicate that the key residues might frame narrow openings that contribute to the permeation pathway. Our findings solve the conundrum of the anomalously low conductance of homomeric 5-HT3A receptors and indicate an important function for the HA-stretch in Cys-loop transmitter-gated ion channels.
Catalysis of the transmembrane transfer of an ion by a channel that opens when a specific extracellular ligand has been bound by the channel complex or one of its constituent parts.
The neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) mediates rapid excitatory responses through ligand-gated channels (5-HT3 receptors). Recombinant expression of the only identified receptor subunit (5-HT3A) yields functional 5-HT3 receptors. However, the conductance of these homomeric receptors (sub-picosiemens) is too small to be resolved directly, and contrasts with a robust channel conductance displayed by neuronal 5-HT3 receptors (9-17 pS). Neuronal 5-HT3 receptors also display a permeability to calcium ions and a current-voltage relationship that differ from those of homomeric receptors. Here we describe a new class of 5-HT3-receptor subunit (5-HT3B). Transcripts of this subunit are co-expressed with the 5-HT3A subunit in the amygdala, caudate and hippocampus. Heteromeric assemblies of 5-HT3A and 5-HT3B subunits display a large single-channel conductance (16 pS), low permeability to calcium ions, and a current-voltage relationship which resembles that of characterized neuronal 5-HT3 channels. The heteromeric receptors also display distinctive pharmacological properties. Surprisingly, the M2 region of the 5-HT3B subunit lacks any of the structural features that are known to promote the conductance of related receptors. In addition to providing a new target for therapeutic agents, the 5-HT3B subunit will be a valuable resource for defining the molecular mechanisms of ion-channel function.
Interacting selectively and non-covalently with serotonin (5-hydroxytryptamine), a monoamine neurotransmitter occurring in the peripheral and central nervous systems, also having hormonal properties.
The 5-hydroxytryptamine3 receptor 5-HT3R has been implicated in gut and cardiac motility and in behavioral disorders. Characteristics of 5-HT3Rs appear to be heterogeneous among species, but human 5-HT3R cDNA has not been identified. We isolated a cDNA encoding 5-HT3R from human hippocampus. The mouse 5-HT3R gene has been reported to generate two alternative splicing isoforms that differ by six amino acids. All of our isolated human clones corresponded to the shorter isoform. Amino acid identities with mouse neuroblastoma N1E-115 and rat brain 5-HT3Rs were 84% for each. Southern blot analysis of human genomic DNA suggested that our cloned transcript encoded a human counterpart for the rodent 5-HT3Rs. This gene was assigned to chromosome 11 using polymerase chain reaction analysis of a human/rodent somatic cell hybrid panel. With the use of Northern blot analysis, 5-HT3R transcripts were identified in human small intestine, colon, and brain regions including hippocampus, amygdala, and striatum. In human heart, 5-HT3R expression was not detectable even with reverse transcriptase-polymerase chain reaction analysis, although it was detectable in mouse heart. Transfection of COS-1 with human 5-HT3R cDNA induced specific binding of the 5-HT3R-selective radioligand [3H]YM060. Human 5-HT3R showed typical characteristics of the 5-HT3R, but its affinity for the 5-HT3R agonist m-chlorophenylbiguanide was much lower than that of rat 5-HT3R. When injected with human 5-HT3R cRNA, the oocytes responded to 5-HT3R agonists with a rapidly developing inward current. The potency of the agonists to induce inward current paralleled that to compete with the radioligand binding, and 2-methyl-5-hydroxytryptamine, a partial agonist for mouse 5-HT3R, was a full agonist for human 5-HT3R. Our data revealed that the 5-HT3R molecule has interspecies differences in both tissue distribution and functional profile.
Combining with the biogenic amine serotonin and transmitting the signal across the membrane by activating an associated G-protein. Serotonin (5-hydroxytryptamine) is a neurotransmitter and hormone found in vertebrates and invertebrates.
The 5-hydroxytryptamine3 receptor 5-HT3R has been implicated in gut and cardiac motility and in behavioral disorders. Characteristics of 5-HT3Rs appear to be heterogeneous among species, but human 5-HT3R cDNA has not been identified. We isolated a cDNA encoding 5-HT3R from human hippocampus. The mouse 5-HT3R gene has been reported to generate two alternative splicing isoforms that differ by six amino acids. All of our isolated human clones corresponded to the shorter isoform. Amino acid identities with mouse neuroblastoma N1E-115 and rat brain 5-HT3Rs were 84% for each. Southern blot analysis of human genomic DNA suggested that our cloned transcript encoded a human counterpart for the rodent 5-HT3Rs. This gene was assigned to chromosome 11 using polymerase chain reaction analysis of a human/rodent somatic cell hybrid panel. With the use of Northern blot analysis, 5-HT3R transcripts were identified in human small intestine, colon, and brain regions including hippocampus, amygdala, and striatum. In human heart, 5-HT3R expression was not detectable even with reverse transcriptase-polymerase chain reaction analysis, although it was detectable in mouse heart. Transfection of COS-1 with human 5-HT3R cDNA induced specific binding of the 5-HT3R-selective radioligand [3H]YM060. Human 5-HT3R showed typical characteristics of the 5-HT3R, but its affinity for the 5-HT3R agonist m-chlorophenylbiguanide was much lower than that of rat 5-HT3R. When injected with human 5-HT3R cRNA, the oocytes responded to 5-HT3R agonists with a rapidly developing inward current. The potency of the agonists to induce inward current paralleled that to compete with the radioligand binding, and 2-methyl-5-hydroxytryptamine, a partial agonist for mouse 5-HT3R, was a full agonist for human 5-HT3R. Our data revealed that the 5-HT3R molecule has interspecies differences in both tissue distribution and functional profile.
Catalysis of the transmembrane transfer of a cation by a channel that opens when a specific extracellular ligand has been bound by the channel complex or one of its constituent parts, and that is activated by serotonin.
The 5-hydroxytryptamine3 receptor 5-HT3R has been implicated in gut and cardiac motility and in behavioral disorders. Characteristics of 5-HT3Rs appear to be heterogeneous among species, but human 5-HT3R cDNA has not been identified. We isolated a cDNA encoding 5-HT3R from human hippocampus. The mouse 5-HT3R gene has been reported to generate two alternative splicing isoforms that differ by six amino acids. All of our isolated human clones corresponded to the shorter isoform. Amino acid identities with mouse neuroblastoma N1E-115 and rat brain 5-HT3Rs were 84% for each. Southern blot analysis of human genomic DNA suggested that our cloned transcript encoded a human counterpart for the rodent 5-HT3Rs. This gene was assigned to chromosome 11 using polymerase chain reaction analysis of a human/rodent somatic cell hybrid panel. With the use of Northern blot analysis, 5-HT3R transcripts were identified in human small intestine, colon, and brain regions including hippocampus, amygdala, and striatum. In human heart, 5-HT3R expression was not detectable even with reverse transcriptase-polymerase chain reaction analysis, although it was detectable in mouse heart. Transfection of COS-1 with human 5-HT3R cDNA induced specific binding of the 5-HT3R-selective radioligand [3H]YM060. Human 5-HT3R showed typical characteristics of the 5-HT3R, but its affinity for the 5-HT3R agonist m-chlorophenylbiguanide was much lower than that of rat 5-HT3R. When injected with human 5-HT3R cRNA, the oocytes responded to 5-HT3R agonists with a rapidly developing inward current. The potency of the agonists to induce inward current paralleled that to compete with the radioligand binding, and 2-methyl-5-hydroxytryptamine, a partial agonist for mouse 5-HT3R, was a full agonist for human 5-HT3R. Our data revealed that the 5-HT3R molecule has interspecies differences in both tissue distribution and functional profile.
The whole of the physical, chemical, and biochemical processes carried out by multicellular organisms to break down ingested nutrients into components that may be easily absorbed and directed into metabolism.
The 5-hydroxytryptamine3 receptor 5-HT3R has been implicated in gut and cardiac motility and in behavioral disorders. Characteristics of 5-HT3Rs appear to be heterogeneous among species, but human 5-HT3R cDNA has not been identified. We isolated a cDNA encoding 5-HT3R from human hippocampus. The mouse 5-HT3R gene has been reported to generate two alternative splicing isoforms that differ by six amino acids. All of our isolated human clones corresponded to the shorter isoform. Amino acid identities with mouse neuroblastoma N1E-115 and rat brain 5-HT3Rs were 84% for each. Southern blot analysis of human genomic DNA suggested that our cloned transcript encoded a human counterpart for the rodent 5-HT3Rs. This gene was assigned to chromosome 11 using polymerase chain reaction analysis of a human/rodent somatic cell hybrid panel. With the use of Northern blot analysis, 5-HT3R transcripts were identified in human small intestine, colon, and brain regions including hippocampus, amygdala, and striatum. In human heart, 5-HT3R expression was not detectable even with reverse transcriptase-polymerase chain reaction analysis, although it was detectable in mouse heart. Transfection of COS-1 with human 5-HT3R cDNA induced specific binding of the 5-HT3R-selective radioligand [3H]YM060. Human 5-HT3R showed typical characteristics of the 5-HT3R, but its affinity for the 5-HT3R agonist m-chlorophenylbiguanide was much lower than that of rat 5-HT3R. When injected with human 5-HT3R cRNA, the oocytes responded to 5-HT3R agonists with a rapidly developing inward current. The potency of the agonists to induce inward current paralleled that to compete with the radioligand binding, and 2-methyl-5-hydroxytryptamine, a partial agonist for mouse 5-HT3R, was a full agonist for human 5-HT3R. Our data revealed that the 5-HT3R molecule has interspecies differences in both tissue distribution and functional profile.
The 5-hydroxytryptamine3 receptor 5-HT3R has been implicated in gut and cardiac motility and in behavioral disorders. Characteristics of 5-HT3Rs appear to be heterogeneous among species, but human 5-HT3R cDNA has not been identified. We isolated a cDNA encoding 5-HT3R from human hippocampus. The mouse 5-HT3R gene has been reported to generate two alternative splicing isoforms that differ by six amino acids. All of our isolated human clones corresponded to the shorter isoform. Amino acid identities with mouse neuroblastoma N1E-115 and rat brain 5-HT3Rs were 84% for each. Southern blot analysis of human genomic DNA suggested that our cloned transcript encoded a human counterpart for the rodent 5-HT3Rs. This gene was assigned to chromosome 11 using polymerase chain reaction analysis of a human/rodent somatic cell hybrid panel. With the use of Northern blot analysis, 5-HT3R transcripts were identified in human small intestine, colon, and brain regions including hippocampus, amygdala, and striatum. In human heart, 5-HT3R expression was not detectable even with reverse transcriptase-polymerase chain reaction analysis, although it was detectable in mouse heart. Transfection of COS-1 with human 5-HT3R cDNA induced specific binding of the 5-HT3R-selective radioligand [3H]YM060. Human 5-HT3R showed typical characteristics of the 5-HT3R, but its affinity for the 5-HT3R agonist m-chlorophenylbiguanide was much lower than that of rat 5-HT3R. When injected with human 5-HT3R cRNA, the oocytes responded to 5-HT3R agonists with a rapidly developing inward current. The potency of the agonists to induce inward current paralleled that to compete with the radioligand binding, and 2-methyl-5-hydroxytryptamine, a partial agonist for mouse 5-HT3R, was a full agonist for human 5-HT3R. Our data revealed that the 5-HT3R molecule has interspecies differences in both tissue distribution and functional profile.
The 5-hydroxytryptamine3 receptor 5-HT3R has been implicated in gut and cardiac motility and in behavioral disorders. Characteristics of 5-HT3Rs appear to be heterogeneous among species, but human 5-HT3R cDNA has not been identified. We isolated a cDNA encoding 5-HT3R from human hippocampus. The mouse 5-HT3R gene has been reported to generate two alternative splicing isoforms that differ by six amino acids. All of our isolated human clones corresponded to the shorter isoform. Amino acid identities with mouse neuroblastoma N1E-115 and rat brain 5-HT3Rs were 84% for each. Southern blot analysis of human genomic DNA suggested that our cloned transcript encoded a human counterpart for the rodent 5-HT3Rs. This gene was assigned to chromosome 11 using polymerase chain reaction analysis of a human/rodent somatic cell hybrid panel. With the use of Northern blot analysis, 5-HT3R transcripts were identified in human small intestine, colon, and brain regions including hippocampus, amygdala, and striatum. In human heart, 5-HT3R expression was not detectable even with reverse transcriptase-polymerase chain reaction analysis, although it was detectable in mouse heart. Transfection of COS-1 with human 5-HT3R cDNA induced specific binding of the 5-HT3R-selective radioligand [3H]YM060. Human 5-HT3R showed typical characteristics of the 5-HT3R, but its affinity for the 5-HT3R agonist m-chlorophenylbiguanide was much lower than that of rat 5-HT3R. When injected with human 5-HT3R cRNA, the oocytes responded to 5-HT3R agonists with a rapidly developing inward current. The potency of the agonists to induce inward current paralleled that to compete with the radioligand binding, and 2-methyl-5-hydroxytryptamine, a partial agonist for mouse 5-HT3R, was a full agonist for human 5-HT3R. Our data revealed that the 5-HT3R molecule has interspecies differences in both tissue distribution and functional profile.
The directed movement of substances (such as macromolecules, small molecules, ions) into, out of or within a cell, or between cells, or within a multicellular organism by means of some agent such as a transporter or pore.
NASUniProtKB Annot
Pathways
According to Reactome, this protein belongs to the following pathway:
Transmembrane transport of small molecules REACT_15518
Note
The HA-stretch region of HTR3A seems to be responsible for the low conductance of HTR3A homomers compared to that of HTR3A/HTR3B heteromers.
Protein involved in the transport of ions. Such proteins are usually transmembrane and mediate a movement of ions across cell membranes. Transport may be passive (facilitated diffusion; down the electrochemical gradient), or active (against the electrochemical gradient). Active transport requires energy which may come from light, oxidation reactions, ATP hydrolysis, or cotransport of other ions or molecules.
Protein involved in the transport of a molecule (metabolite, protein, etc), a ion or an electron across cell membranes, inside the cell or in a tissue fluid.
Protein which is part of a transmembrane protein complex that forms a hydrophilic channel across the lipid bilayer through which specific inorganic ions can diffuse down their electrochemical gradients. The channels are usually gated and only open in response to a specific stimulus, such as a change in membrane potential (voltage-gated) or the binding of a ligand (ligand-gated channel).
Protein which forms or is a component of a ligand-gated channel. Ligand-gated channels are transmembrane ion channels whose permeability is increased by the binding of a specific ligand, such as neurotransmitters, ionositol triphosphates, and cyclic nucleotides.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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