{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The serotonin 2B receptor (HTR2B), a G protein‐coupled receptor for serotonin, has emerged as a pleiotropic regulator across multiple physiological systems. Structural and signaling studies reveal that HTR2B can exhibit biased signaling profiles—for instance, certain ergoline compounds preferentially activate β‐arrestin pathways via HTR2B, which may underlie some of their hallucinogenic properties."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the central nervous system, studies indicate that HTR2B is integral to behavioral responses, as shown by the absence of drug‐induced sensitization and reinforcement in receptor knockout models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, HTR2B expressed on hypothalamic and other neuronal populations appears to contribute to energy homeostasis and appetite regulation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", with genetic variant studies also implicating HTR2B in modulating body weight and adiposity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cardiovascular system, HTR2B is critical for cardiomyocyte development and growth; receptor activation in cardiac fibroblasts drives cytokine production (e.g., interleukin‐1β, tumor necrosis factor‐α) that underlies isoproterenol-induced hypertrophy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Similarly, in the skeletal system, HTR2B supports osteoblast proliferation and differentiation—a protective function, as evidenced by osteopenia that develops in HTR2B-deficient mice."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Metabolically, HTR2B activation in pancreatic islet beta cells enhances glucose-stimulated insulin secretion via modulation of calcium oscillations and mitochondrial activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In the gastrointestinal tract, HTR2B signaling facilitates the proliferation and maintenance of interstitial cells of Cajal, which are essential for normal gut motility; loss of receptor signaling compromises these networks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the pulmonary vasculature, antagonism of HTR2B has been shown to prevent abnormal vascular remodeling and pulmonary arterial hypertension in BMPR2 mutant models by limiting aberrant SRC kinase activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, altered HTR2B expression in non-neuronal tissues such as skin and ovary has been associated with changes in cell proliferation and differentiation. In ovarian tissues, for example, decreased HTR2B expression in invasive carcinomas correlates with enhanced disease dissemination, suggesting a possible tumor-suppressive or differentiation-promoting role."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these diverse studies underscore the multifaceted functions of HTR2B in modulating neuronal behavior, energy and metabolic homeostasis, cardiovascular and skeletal integrity, and cellular proliferation. The receptor’s widespread influence across tissues highlights its potential as a therapeutic target for conditions ranging from mood and metabolic disorders to cardiac hypertrophy, osteoporosis, pulmonary hypertension, and certain cancers.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daniel Wacker, Chong Wang, Vsevolod Katritch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural features for functional selectivity at serotonin receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1232808"}], "href": "https://doi.org/10.1126/science.1232808"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23519215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23519215"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Stéphane Doly, Jesus Bertran-Gonzalez, Jacques Callebert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of serotonin via 5-HT2B receptors in the reinforcing effects of MDMA in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0007952"}], "href": "https://doi.org/10.1371/journal.pone.0007952"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19956756"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19956756"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Vijay K Yadav, Franck Oury, Nina Suda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2009.06.051"}], "href": "https://doi.org/10.1016/j.cell.2009.06.051"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19737523"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19737523"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Soo Heon Kwak, Byoung Lae Park, Hail Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of variations in TPH1 and HTR2B with gestational weight gain and measures of obesity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Obesity (Silver Spring) (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/oby.2011.253"}], "href": "https://doi.org/10.1038/oby.2011.253"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21836641"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21836641"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Fabrice Jaffré, Jacques Callebert, Alexandre Sarre, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.CIR.0000139856.20505.57"}], "href": "https://doi.org/10.1161/01.CIR.0000139856.20505.57"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15302781"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15302781"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "C Collet, C Schiltz, V Geoffroy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.07-9209com"}], "href": "https://doi.org/10.1096/fj.07-9209com"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17846081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17846081"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hedvig Bennet, Inês G Mollet, Alexander Balhuizen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-015-3847-6"}], "href": "https://doi.org/10.1007/s00125-015-3847-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26733006"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26733006"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "V S Tharayil, M M Wouters, J E Stanich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lack of serotonin 5-HT2B receptor alters proliferation and network volume of interstitial cells of Cajal in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogastroenterol Motil (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2982.2009.01435.x"}], "href": "https://doi.org/10.1111/j.1365-2982.2009.01435.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19941613"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19941613"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "James D West, Erica J Carrier, Nathaniel C Bloodworth, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension."}]}, {"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.0148657"}], "href": "https://doi.org/10.1371/journal.pone.0148657"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26863209"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26863209"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Andrzej Slominski, Alexander Pisarchik, Blazej Zbytek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional activity of serotoninergic and melatoninergic systems expressed in the skin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.10287"}], "href": "https://doi.org/10.1002/jcp.10287"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12767050"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12767050"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Rudi Henriksen, Nishtman Dizeyi, Per-Anders Abrahamsson "}, {"type": "b", "children": [{"type": "t", "text": "Expression of serotonin receptors 5-HT1A, 5-HT1B, 5-HT2B and 5-HT4 in ovary and in ovarian tumours."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anticancer Res (2012)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22493371"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22493371"}]}]}]}