{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The HTR3A gene encodes a key subunit of the 5‐HT3 receptor, a ligand‐gated ion channel that mediates fast excitatory serotonin transmission in both the central and peripheral nervous systems. Structural and electrophysiological studies have revealed that homomeric 5‐HT3A receptors exhibit an intrinsically low single‐channel conductance—a feature determined in part by a unique “HA‐stretch” within the large intracellular loop that modulates ion permeation and receptor gating."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, targeted mutagenesis has pinpointed critical cation–π interactions in the ligand binding domain that define agonist recognition and receptor activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In clinical contexts, genetic variations in HTR3A have been implicated in modulating the efficacy of antidepressant treatment and influencing mood and emotional processing. Polymorphisms in HTR3A are associated with differential responses to selective serotonin reuptake inhibitors and have been linked to altered amygdala and prefrontal cortex reactivity, thereby contributing to the risk and clinical presentation of mood and behavioral disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in neurotransmission and affect regulation, 5‐HT3A receptor–mediated signaling participates in diverse physiological processes. In pancreatic β cells, for instance, autocrine/paracrine activation of 5‐HT3 receptors is essential for lowering the glucose threshold for insulin secretion during pregnancy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In central pain circuits, descending serotonergic inputs acting through 5‐HT3 receptors contribute to the sensitization of central terminals and the modulation of hyperalgesia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, developmental studies have demonstrated that 5‐HT3A receptor expression marks a subpopulation of migrating cortical interneurons, where its activation is required in a cell‐autonomous manner for the proper migration and laminar placement of reelin‐expressing interneurons in the neocortex."}, {"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": "Michaela Jansen, Moez Bali, Myles H Akabas "}, {"type": "b", "children": [{"type": "t", "text": "Modular design of Cys-loop ligand-gated ion channels: functional 5-HT3 and GABA rho1 receptors lacking the large cytoplasmic M3M4 loop."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Gen Physiol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1085/jgp.200709896"}], "href": "https://doi.org/10.1085/jgp.200709896"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18227272"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18227272"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Darren L Beene, Gabriel S Brandt, Wenge Zhong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi020266d"}], "href": "https://doi.org/10.1021/bi020266d"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12162741"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12162741"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "M Kato, A Serretti "}, {"type": "b", "children": [{"type": "t", "text": "Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mp.2008.116"}], "href": "https://doi.org/10.1038/mp.2008.116"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18982004"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18982004"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Masaki Kato, Tsuyoshi Fukuda, Masataka Wakeno, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fluvoxamine efficacy and adverse drug reactions in depressed Japanese patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuropsychobiology (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000094727"}], "href": "https://doi.org/10.1159/000094727"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16874005"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16874005"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "B Niesler, T Flohr, M M Nöthen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association between the 5' UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacogenetics (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/00008571-200108000-00002"}], "href": "https://doi.org/10.1097/00008571-200108000-00002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11505217"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11505217"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Tetsuya Iidaka, Norio Ozaki, Atsushi Matsumoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.5261-04.2005"}], "href": "https://doi.org/10.1523/JNEUROSCI.5261-04.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16000636"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16000636"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Justine M Gatt, Leanne M Williams, Peter R Schofield, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impact of the HTR3A gene with early life trauma on emotional brain networks and depressed mood."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Depress Anxiety (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/da.20726"}], "href": "https://doi.org/10.1002/da.20726"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20694966"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20694966"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Mica Ohara-Imaizumi, Hail Kim, Masashi Yoshida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serotonin regulates glucose-stimulated insulin secretion from pancreatic β cells during pregnancy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1310953110"}], "href": "https://doi.org/10.1073/pnas.1310953110"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24218571"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24218571"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yu Shin Kim, Yuxia Chu, Liang Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2013.12.011"}], "href": "https://doi.org/10.1016/j.neuron.2013.12.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24462040"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24462040"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Sahana Murthy, Mathieu Niquille, Nicolas Hurni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serotonin receptor 3A controls interneuron migration into the neocortex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms6524"}], "href": "https://doi.org/10.1038/ncomms6524"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25409778"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25409778"}]}]}]}