{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have expanded our understanding of TAS2R46 beyond its traditional role in taste perception by demonstrating its expression in extraoral tissues such as mesenchymal stromal cells (MSC) and vascular smooth muscle cells (VSMCs). Activation of TAS2R46 by bitter compounds like denatonium in these cells triggers intracellular signaling events—including increased intracellular Ca²⁺ release, decreased cAMP levels, and enhanced extracellular ATP release—that promote functional responses such as vasodilation, as illustrated by the significant drop in blood pressure observed in vivo."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn airway smooth muscle cells, TAS2R46 exhibits a unique mode of action. Rather than directly inducing a Ca²⁺ signal, stimulation with the specific agonist absinthin reduces histamine-induced cytosolic Ca²⁺ increases while concurrently enhancing Ca²⁺ uptake into mitochondria. This receptor-mediated Ca²⁺ shuttling depends on intact TAS2R46 expression and involves key signaling intermediates such as the exchange protein directly activated by cAMP (EPAC) and cytoskeletal dynamics, underscoring an unconventional link between plasma membrane receptor activity and mitochondrial Ca²⁺ regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural insights into TAS2R46 have been provided by high-resolution cryo-electron microscopy studies that captured both ligand-bound (with strychnine) and apo receptor states. These analyses revealed distinct receptor conformations, including a novel “toggle switch” and activation-related motifs, and demonstrated precoupling with a chimeric mini-G protein, thereby laying the groundwork for understanding the molecular basis of ligand recognition and receptor activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in smooth muscle cells, TAS2R46 has also been implicated in immune protection. Activation of TAS2R46 in monocytes and macrophages by absinthin was shown to counteract oxidative stress by diminishing the release of reactive oxygen and nitrogen species and reducing DNA damage. This protective mechanism likely supports the antimicrobial functions of these immune cells while preventing damage from supraphysiological ROS production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther reinforcing the importance of receptor structure for function, mutagenesis and in silico analyses of TAS2R46 have identified that single nucleotide polymorphisms, especially those affecting the fourth transmembrane domain, can critically alter receptor signaling. Such mutations abolish the receptor’s ability to facilitate mitochondrial Ca²⁺ uptake, emphasizing the essential role of this transmembrane region in maintaining the proper signal transduction required for TAS2R46’s diverse cellular functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Troy C Lund, Amanda J Kobs, Ashley Kramer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bone marrow stromal and vascular smooth muscle cells have chemosensory capacity via bitter taste receptor expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0058945"}], "href": "https://doi.org/10.1371/journal.pone.0058945"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23520545"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23520545"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Michiko Yamaki, Hiroki Saito, Kunio Isono, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genotyping Analysis of Bitter-Taste Receptor Genes TAS2R38 and TAS2R46 in Japanese Patients with Gastrointestinal Cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Nutr Sci Vitaminol (Tokyo) (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3177/jnsv.63.148"}], "href": "https://doi.org/10.3177/jnsv.63.148"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28552880"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28552880"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Maria Talmon, Silvia Rossi, Dmitry Lim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Absinthin, an agonist of the bitter taste receptor hTAS2R46, uncovers an ER-to-mitochondria 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": "-shuttling event."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA119.007763"}], "href": "https://doi.org/10.1074/jbc.RA119.007763"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31248983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31248983"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Weixiu Xu, Lijie Wu, Shenhui Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for strychnine activation of human bitter taste receptor TAS2R46."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.abo1633"}], "href": "https://doi.org/10.1126/science.abo1633"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36108005"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36108005"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Maria Talmon, Lara Camillo, Ilaria Vietti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bitter Taste Receptor 46 (hTAS2R46) Protects Monocytes/Macrophages from Oxidative Stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms25137325"}], "href": "https://doi.org/10.3390/ijms25137325"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39000432"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39000432"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Giulia Lecchi, Chiara Mocchetti, Davide Tunesi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Single-Nucleotide Polymorphisms of TAS2R46 Affect the Receptor Downstream Calcium Regulation in Histamine-Challenged Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells13141204"}], "href": "https://doi.org/10.3390/cells13141204"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39056786"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39056786"}]}]}]}