Alternative titles; symbols
HGNC Approved Gene Symbol: HTR3A
Cytogenetic location: 11q23.2 Genomic coordinates (GRCh38): 11:113,975,108-113,990,313 (from NCBI)
Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter in the central and peripheral nervous systems that plays a role in many physiologic processes such as sleep, appetite, thermoregulation, pain perception, hormone secretion, and sexual behavior. Abnormality of the serotonergic system has been implicated in a number of human disorders such as mental depression, migraine, epilepsy, obsessive-compulsive disorder, and affective disorder. Like other neurotransmitters, 5-HT is released into the synaptic junction and exerts its effect on specific receptors on the postsynaptic membranes. Based on differential radioligand binding affinities, several 5-HT receptors have been identified: 5-HT-1A, -1B, -1C, -1D, -2, and -3 (summary by Sparkes et al., 1991; see reviews by Peroutka, 1988 and Paoletti et al., 1990).
Maricq et al. (1991) cloned the mouse 5-hydroxytryptamine receptor 3A (Htr3) gene. Miyake et al. (1995) isolated human HTR3A cDNA from a hippocampus cDNA library. This receptor is a ligand-gated ion channel, whereas all other known 5-HT receptor subtypes are G protein-coupled receptors. The deduced HTR3A protein contains 478 amino acids with a potential signal peptide of 23 residues. Northern blot analysis detected an approximately 2.4-kb transcript in small intestine, colon, and brain regions including the amygdala, hippocampus, and caudate nucleus. Slight signals were detected in spleen, thymus, and prostate. Miyake et al. (1995) presented data suggesting that the tissue distribution of HTR3A is heterogeneous among species.
The single-channel conductance for homomers of HTR3A is 0.4 pS, whereas that for heteromers of HTR3A and HTR3B (604654) is 16 pS. By constructing chimeric HTR3A and HTR3B subunits, Kelley et al. (2003) identified a region, which they called the HA-stretch, that is within the large cytoplasmic loop of the receptor and markedly influences channel conductance. Replacement of 3 arginine residues unique to the HA-stretch of the HTR3A subunit by their HTR3B subunit counterparts increased single-channel conductance 28-fold. Ultrastructural studies of the Torpedo nicotinic acetylcholine receptor indicated that the key residues might frame narrow openings that contribute to the permeation pathway. Kelley et al. (2003) concluded that their findings solved the conundrum of the anomalously low conductance of homomeric HTR3A receptors and indicated an important function of the HA-stretch in cys-loop transmitter-gated ion channels.
Bruss et al. (2000) determined the genomic structure of the HTR3A gene. The gene contains 7 exons and spans approximately 14.5 kb.
Crystal Structure
Hassaine et al. (2014) presented the x-ray structure of a mammalian cysteine-loop receptor, the mouse serotonin 5-HT-3 receptor, at 3.5-angstrom resolution. The structure of the proteolysed receptor, made up of 2 fragments and comprising part of the intracellular domain, was determined in complex with stabilizing nanobodies. The extracellular domain reveals the detailed anatomy of the neurotransmitter-binding site capped by a nanobody. The membrane domain delimits an aqueous pore with a 4.6-angstrom constriction. In the intracellular domain, a bundle of 5 intracellular helices creates a closed vestibule where lateral portals are obstructed by loops.
Cryoelectron Microscopy
Basak et al. (2018) presented 2 serotonin-bound structures of the full-length 5-HT3A receptor in distinct conformations at 3.32- and 3.89-angstrom resolution that revealed the mechanism underlying channel activation. In comparison to the apo 5-HT3A receptor, serotonin-bound states underwent a large twisting motion in the extracellular domain and transmembrane domain, leading to the opening of a 165-angstrom permeation pathway. Notably, this motion results in the creation of lateral portals for ion permeation at the interface of the transmembrane domain and intracellular domain.
Polovinkin et al. (2018) independently reported 4 cryoelectron microscopy structures of the full-length mouse 5-HT3 receptor in complex with the antiemetic drug tropisetron, with serotonin, and with serotonin and a positive allosteric modulator, at 3.2- to 4.5-angstrom resolutions. The tropisetron-bound structure resembled those obtained with an inhibitory nanobody or without ligand. The other structures included an 'open' state and 2 ligand-bound states. Polovinkin et al. (2018) presented computational insights into the dynamics of the structures as well as their pore hydration and free energy profiles, and characterized movements at the gate level and cation accessibility in the pore. Polovinkin et al. (2018) concluded that their data deepened understanding of the gating mechanism of pentameric ligand-gated ion channels and captured ligand binding in unprecedented detail.
Using the mouse Htr3 clone as a probe, Uetz et al. (1994) mapped the human homolog to chromosome 11 by Southern analysis of DNA isolated from monochromosomal rodent/human hybrid cell lines. By somatic cell hybrid analysis, Miyake et al. (1995) mapped the HTR3A gene to chromosome 11. Weiss et al. (1995) used fluorescence in situ hybridization to assign the HTR3 gene to 11q23.1-q23.2. Weiss et al. (1995) pointed out that psychiatric disorders such as schizophrenia and bipolar affective disease have been found to segregate with cytogenetic abnormalities involving chromosome 11 and specifically this region of 11q.
Basak, S., Gicheru, Y., Rao, S., Sansom, M. S. P., Chakrapani, S. Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor. Nature 563: 270-274, 2018. [PubMed: 30401837] [Full Text: https://doi.org/10.1038/s41586-018-0660-7]
Bruss, M., Eucker, T., Gothert, M., Bonisch, H. Exon-intron organization of the human 5-HT-3A receptor gene. Neuropharmacology 39: 308-315, 2000. [PubMed: 10670426] [Full Text: https://doi.org/10.1016/s0028-3908(99)00116-1]
Hassaine, G., Deluz, C., Grasso, L., Wyss, R., Tol, M. B., Hovius, R., Graff, A., Stahlberg, H., Tomizaki, T., Desmyter, A., Moreau, C., Li, X.-D., Poitevin, F., Vogel, H., Nury, H. X-ray structure of the mouse serotonin 5-HT-3 receptor. Nature 512: 276-281, 2014. [PubMed: 25119048] [Full Text: https://doi.org/10.1038/nature13552]
Kelley, S. P., Dunlop, J. I., Kirkness, E. F., Lambert, J. J., Peters, J. A. A cytoplasmic region determines single-channel conductance in 5-HT(3) receptors. Nature 424: 321-324, 2003. [PubMed: 12867984] [Full Text: https://doi.org/10.1038/nature01788]
Maricq, A. V., Peterson, A. S., Brake, A. J., Myers, R. M., Julius, D. Primary structure and functional expression of the 5HT-3 receptor, a serotonin-gated ion channel. Science 254: 432-437, 1991. [PubMed: 1718042] [Full Text: https://doi.org/10.1126/science.1718042]
Miyake, A., Mochizuki, S., Takemoto, Y., Akuzawa, S. Molecular cloning of human 5-hydroxytryptamine-3 receptor: heterogeneity in distribution and function among species. Molec. Pharm. 48: 407-416, 1995. [PubMed: 7565620]
Paoletti, R., Vanhoutte, P. M., Brunello, N., Maggi, F. M. (eds.). Serotonin: From Cell Biology to Pharmacology and Therapeutics. Boston: Kluwer Academic Publ. 1990.
Peroutka, S. J. 5-Hydroxytryptamine receptor subtypes. Annu. Rev. Neurosci. 11: 45-60, 1988. [PubMed: 3284448] [Full Text: https://doi.org/10.1146/annurev.ne.11.030188.000401]
Polovinkin, L., Hassaine, G., Perot, J., Neumann, E., Jensen, A. A., Lefebvre, S. N., Corringer, P.-J., Neyton, J., Chipot, C., Dehez, F., Schoehn, G., Nury, H. Conformational transitions of the serotonin 5-HT3 receptor. Nature 563: 275-279, 2018. [PubMed: 30401839] [Full Text: https://doi.org/10.1038/s41586-018-0672-3]
Sparkes, R. S., Lan, N., Klisak, I., Mohandas, T., Diep, A., Kojis, T., Heinzmann, C., Shih, J. C. Assignment of a serotonin 5HT-2 receptor gene (HTR2) to human chromosome 13q14-q21 and mouse chromosome 14. Genomics 9: 461-465, 1991. [PubMed: 2032718] [Full Text: https://doi.org/10.1016/0888-7543(91)90411-7]
Uetz, P., Abdelatty, F., Villarroel, A., Rappold, G., Weiss, B., Koenen, M. Organisation of the murine 5-HT-3 receptor gene and assignment to human chromosome 11. FEBS Lett. 339: 302-306, 1994. [PubMed: 8112471] [Full Text: https://doi.org/10.1016/0014-5793(94)80435-4]
Weiss, B., Mertz, A., Schrock, E., Koenen, M., Rappold, G. Assignment of a human homolog of the mouse Htr3 receptor gene to chromosome 11q23.1-q23.2. Genomics 29: 304-305, 1995. [PubMed: 8530095] [Full Text: https://doi.org/10.1006/geno.1995.1254]