{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTrace amine‐associated receptor 1 (TAAR1) is a G protein‐coupled receptor activated by endogenous trace amines and amino acid metabolites. In the central nervous system, TAAR1 modulates monoaminergic circuits by regulating neuronal excitability—partly through tonic activation of inwardly rectifying K⁺ channels—and by influencing dopamine receptor signaling, including the potency of dopamine at D2 receptors. These actions suggest that TAAR1 plays a key role in setting the basal firing rates of dopamine neurons in regions such as the ventral tegmental area, and that it may exhibit constitutive activity or be tonically activated by ambient ligands."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n \nDisruption or modulation of TAAR1 signaling has broad implications for neuropsychiatric conditions and substance abuse. Studies have demonstrated that TAAR1 not only regulates the responsiveness of D2 receptors through direct physical interactions and heterodimer formation but also modulates dopaminergic and serotonergic transmission in response to psychostimulants. In knockout models, absence of TAAR1 led to enhanced psychostimulant-induced locomotion, altered neurochemical release profiles, and changes in reward‐related behavior. These findings highlight a receptor role in signaling cascades (including ERK1/2 pathways) that impact both acute and adaptive responses to drugs such as amphetamine, methamphetamine, and MDMA."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "14"}]}, {"type": "t", "text": "\n \nBeyond its central actions, TAAR1 is expressed in peripheral tissues—including immune cells and certain cancer cell types—where it contributes to chemotaxis, cytokine secretion, and cellular viability. Structural and pharmacological studies have identified a conserved primary amine recognition pocket along with additional binding sites that confer signaling bias between Gs and Gq pathways. These molecular insights explain how diverse endogenous ligands and clinically relevant drugs interact with TAAR1, and they underscore species-specific variations that are important for personalized therapeutic approaches. Furthermore, modulation of TAAR1 activity has been linked to regulation of inflammatory responses (for example, in microglia) and protection against drug-induced toxicity through anti-apoptotic mechanisms, suggesting new avenues for treating neurodegenerative diseases and certain cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daniel A Nelson, Melanie D Tolbert, Sam J Singh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of neuronal trace amine-associated receptor (Taar) mRNAs in leukocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroimmunol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jneuroim.2007.08.006"}], "href": "https://doi.org/10.1016/j.jneuroim.2007.08.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17900709"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17900709"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Anita H Lewin, Hernán A Navarro, S Wayne Mascarella "}, {"type": "b", "children": [{"type": "t", "text": "Structure-activity correlations for beta-phenethylamines at human trace amine receptor 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bioorg Med Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bmc.2008.06.009"}], "href": "https://doi.org/10.1016/j.bmc.2008.06.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18602830"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18602830"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Amyaouch Bradaia, Gerhard Trube, Henri Stalder, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0906522106"}], "href": "https://doi.org/10.1073/pnas.0906522106"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19892733"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19892733"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Gregory M Miller "}, {"type": "b", "children": [{"type": "t", "text": "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2010.07109.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2010.07109.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21073468"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21073468"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Stefano Espinoza, Ali Salahpour, Bernard Masri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional interaction between trace amine-associated receptor 1 and dopamine D2 receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.111.073304"}], "href": "https://doi.org/10.1124/mol.111.073304"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21670104"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21670104"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Michael W Panas, Zhihua Xie, Helen N Panas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trace amine associated receptor 1 signaling in activated lymphocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroimmune Pharmacol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11481-011-9321-4"}], "href": "https://doi.org/10.1007/s11481-011-9321-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22038157"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22038157"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Cindy Achat-Mendes, Laurie J Lynch, Katherine A Sullivan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pharmacol Biochem Behav (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.pbb.2011.10.025"}], "href": "https://doi.org/10.1016/j.pbb.2011.10.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22079347"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22079347"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Benjamin Di Cara, Roberto Maggio, Gabriella Aloisi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.2502-11.2011"}], "href": "https://doi.org/10.1523/JNEUROSCI.2502-11.2011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22114263"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22114263"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Agne Babusyte, Matthias Kotthoff, Julia Fiedler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1189/jlb.0912433"}], "href": "https://doi.org/10.1189/jlb.0912433"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23315425"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23315425"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Xiao Shi, Nicole A R Walter, John H Harkness, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic Polymorphisms Affect Mouse and Human Trace Amine-Associated Receptor 1 Function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0152581"}], "href": "https://doi.org/10.1371/journal.pone.0152581"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27031617"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27031617"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jibin John, Prachi Kukshal, Triptish Bhatia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Possible role of rare variants in Trace amine associated receptor 1 in schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Schizophr Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.schres.2017.02.020"}], "href": "https://doi.org/10.1016/j.schres.2017.02.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28242106"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28242106"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Mallory S Pitts, Josh N McShane, Marius C Hoener, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TAAR1 levels and sub-cellular distribution are cell line but not breast cancer subtype specific."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Histochem Cell Biol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00418-019-01791-7"}], "href": "https://doi.org/10.1007/s00418-019-01791-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31111198"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31111198"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Xiao Shi, Tracy L Swanson, Nicholas B Miner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of Trace Amine-Associated Receptor 1 Stimulates an Antiapoptotic Signal Cascade via Extracellular Signal-Regulated Kinase 1/2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pharmacol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1124/mol.119.116798"}], "href": "https://doi.org/10.1124/mol.119.116798"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31409621"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31409621"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Jennifer M Loftis, Michael Lasarev, Xiao Shi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trace amine-associated receptor gene polymorphism increases drug craving in individuals with methamphetamine dependence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0220270"}], "href": "https://doi.org/10.1371/journal.pone.0220270"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31600226"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31600226"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "D Almeida-Santos, A C Duarte, I Gonçalves, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cadaverine and Spermine Elicit Ca"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "2+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " Uptake in Human CP Cells via a Trace Amine-Associated Receptor 1 Dependent Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Neurosci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12031-020-01684-8"}], "href": "https://doi.org/10.1007/s12031-020-01684-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32816235"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32816235"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Tilman L R Vogelsang, Aurelia Vattai, Elisa Schmoeckel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trace Amine-Associated Receptor 1 (TAAR1) Is a Positive Prognosticator for Epithelial Ovarian Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms22168479"}], "href": "https://doi.org/10.3390/ijms22168479"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34445181"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34445181"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Yazen Alnefeesi, Jocelyn K Tamura, Leanna M W Lui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trace amine-associated receptor 1 (TAAR1): Potential application in mood disorders: A systematic review."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosci Biobehav Rev (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neubiorev.2021.09.020"}], "href": "https://doi.org/10.1016/j.neubiorev.2021.09.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34537265"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34537265"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "David A Barnes, Dylan A Galloway, Marius C Hoener, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TAAR1 Expression in Human Macrophages and Brain Tissue: A Potential Novel Facet of MS Neuroinflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms222111576"}], "href": "https://doi.org/10.3390/ijms222111576"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34769007"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34769007"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Anna V Glyakina, Constantine D Pavlov, Julia V Sopova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Search for Structural Basis of Interactions of Biogenic Amines with Human TAAR1 and TAAR6 Receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms23010209"}], "href": "https://doi.org/10.3390/ijms23010209"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35008636"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35008636"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Claudia Matteucci, Ridvan Nepravishta, Ayele Argaw-Denboba, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymosin α1 interacts with Galectin-1 modulating the β-galactosides affinity and inducing alteration in the biological activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Immunopharmacol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.intimp.2023.110113"}], "href": "https://doi.org/10.1016/j.intimp.2023.110113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37028279"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37028279"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Beatrice Polini, Caterina Ricardi, Andrea Bertolini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "T1AM/TAAR1 System Reduces Inflammatory Response and β-Amyloid Toxicity in Human Microglial HMC3 Cell Line."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms241411569"}], "href": "https://doi.org/10.3390/ijms241411569"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37511328"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37511328"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Zheng Xu, Lulu Guo, Jingjing Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ligand recognition and G-protein coupling of trace amine receptor TAAR1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-023-06804-z"}], "href": "https://doi.org/10.1038/s41586-023-06804-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37935376"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37935376"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Pan Shang, Naikang Rong, Jing-Jing Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural and signaling mechanisms of TAAR1 enabled preferential agonist design."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2023.10.014"}], "href": "https://doi.org/10.1016/j.cell.2023.10.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37963465"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37963465"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Gregory Zilberg, Alexandra K Parpounas, Audrey L Warren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular basis of human trace amine-associated receptor 1 activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-023-44601-4"}], "href": "https://doi.org/10.1038/s41467-023-44601-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38168118"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38168118"}]}]}]}