{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The HTR3B gene encodes the 5‐HT₃ receptor β subunit, a critical modulatory component of the ligand‐gated ion channel that mediates fast serotonergic neurotransmission. When coassembled with the 5‐HT₃ receptor A subunit, the β subunit profoundly alters the receptor’s biophysical properties by markedly increasing single‐channel conductance and changing kinetic parameters such as deactivation, desensitization, and mean open time (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition to these fundamental biophysical effects, several genetic variants in HTR3B—most notably the common Tyr129Ser (Y129S) substitution—have been associated with vulnerability to neuropsychiatric and substance use disorders, including heroin and alcohol dependence, as well as with major depression and eating disorders (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": " Moreover, noncoding variants—including promoter deletions in HTR3B—are linked to altered responses to pharmacotherapy; for instance, they predispose patients to increased nausea and vomiting with selective serotonin reuptake inhibitors (SSRIs) and chemotherapeutic agents (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " Functional studies further reveal that specific residue substitutions in the intracellular domains of the 5‐HT₃B subunit modulate receptor assembly and trafficking by exposing or masking endoplasmic reticulum retention signals, thereby influencing cell surface expression and overall receptor function (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, interactive genetic effects between HTR3B, other serotonergic receptor genes (such as HTR3A), and the serotonin transporter gene (SLC6A4) emphasize the pivotal role of the 5‐HT₃ receptor complex in regulating downstream circuits related to mood, impulsivity, reward, and pain processing (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stephen P Kelley, James I Dunlop, Ewen F Kirkness, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A cytoplasmic region determines single-channel conductance in 5-HT3 receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature01788"}], "href": "https://doi.org/10.1038/nature01788"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12867984"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12867984"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Karen Krzywkowski, Paul A Davies, Paula L Feinberg-Zadek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0708454105"}], "href": "https://doi.org/10.1073/pnas.0708454105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18184810"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18184810"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "O Levran, D Londono, K O'Hara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic susceptibility to heroin addiction: a candidate gene association study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Brain Behav (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1601-183X.2008.00410.x"}], "href": "https://doi.org/10.1111/j.1601-183X.2008.00410.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18518925"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18518925"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "M-A Enoch, E Gorodetsky, C Hodgkinson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mp.2010.94"}], "href": "https://doi.org/10.1038/mp.2010.94"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20838391"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20838391"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kazuo Yamada, Eiji Hattori, Yoshimi Iwayama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Psychiatry (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopsych.2005.11.008"}], "href": "https://doi.org/10.1016/j.biopsych.2005.11.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16487942"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16487942"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Christian Hammer, Johannes Kapeller, Max Endele, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional variants of the serotonin receptor type 3A and B gene are associated with eating disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacogenet Genomics (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/FPC.0b013e32833132b3"}], "href": "https://doi.org/10.1097/FPC.0b013e32833132b3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19741568"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19741568"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Pierre-Benoit Tremblay, Rolf Kaiser, Orhan Sezer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2003.05.164"}], "href": "https://doi.org/10.1200/JCO.2003.05.164"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12775740"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12775740"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "T Sugai, Y Suzuki, K Sawamura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The effect of 5-hydroxytryptamine 3A and 3B receptor genes on nausea induced by paroxetine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacogenomics J (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.tpj.6500382"}], "href": "https://doi.org/10.1038/sj.tpj.6500382"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16534507"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16534507"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Henrik Rueffert, Volker Thieme, Jan Wallenborn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Do variations in the 5-HT3A and 5-HT3B serotonin receptor genes (HTR3A and HTR3B) influence the occurrence of postoperative vomiting?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anesth Analg (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1213/ane.0b013e3181b2359b"}], "href": "https://doi.org/10.1213/ane.0b013e3181b2359b"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19713259"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19713259"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Gary W Boyd, Anne I Doward, Ewen F Kirkness, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cell surface expression of 5-hydroxytryptamine type 3 receptors is controlled by an endoplasmic reticulum retention signal."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M304938200"}], "href": "https://doi.org/10.1074/jbc.M304938200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12750374"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12750374"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Chamindi Seneviratne, Jason Franklin, Katherine Beckett, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association, interaction, and replication analysis of genes encoding serotonin transporter and 5-HT3 receptor subunits A and B in alcohol dependence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-013-1319-y"}], "href": "https://doi.org/10.1007/s00439-013-1319-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23757001"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23757001"}]}]}]}