Journal articles: 'Serotonylation'

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Williams, Erin R. "Chromatin serotonylation limits differentiation." Science Signaling 12, no. 576 (April 9, 2019): eaau2218. http://dx.doi.org/10.1126/scisignal.aau2218.

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Penumatsa, K. C., and B. L. Fanburg. "Transglutaminase 2-mediated serotonylation in pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 306, no. 4 (February 15, 2014): L309—L315. http://dx.doi.org/10.1152/ajplung.00321.2013.

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The monoamine serotonin (5-HT) has been previously implicated in pulmonary arterial remodeling and is considered a potential therapeutic target for the disease pulmonary arterial hypertension (PAH). More recently, it has been recognized that the enzyme tissue transglutaminase (TG2) mediates cross-linking of proteins with 5-HT, a posttranslational process of monoaminylation known as “serotonylation.” TG2 activity and serotonylation of protein participate in both smooth muscle proliferation and contraction produced by 5-HT. Indeed, markedly increased TG2 activity has now been identified in lung tissue of an experimental rodent model of pulmonary hypertension, and elevated serotonylation of fibronectin and the signaling molecule Rho, downstream products of transglutamidation, have been found in blood of patients with PAH. The basic mechanism by which TG2 is activated and the potential role(s) of serotonylated proteins in pulmonary hypertension remain a mystery. In the present review we have tried to address the current understanding of 5-HT metabolism in pulmonary hypertension and relate it to what is currently known about the evolving cellular process of serotonylation.

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Abdala-Valencia, Hiam, Sergejs Berdnikovs, Christine A. McCary, Daniela Urick, Riti Mahadevia, Michelle E. Marchese, Kelsey Swartz, Lakiea Wright, Gökhan M. Mutlu, and Joan M. Cook-Mills. "Inhibition of allergic inflammation by supplementation with 5-hydroxytryptophan." American Journal of Physiology-Lung Cellular and Molecular Physiology 303, no. 8 (October 15, 2012): L642—L660. http://dx.doi.org/10.1152/ajplung.00406.2011.

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Clinical reports indicate that patients with allergy/asthma commonly have associated symptoms of anxiety/depression. Anxiety/depression can be reduced by 5-hydroxytryptophan (5-HTP) supplementation. However, it is not known whether 5-HTP reduces allergic inflammation. Therefore, we determined whether 5-HTP supplementation reduces allergic inflammation. We also determined whether 5-HTP decreases passage of leukocytes through the endothelial barrier by regulating endothelial cell function. For these studies, C57BL/6 mice were supplemented with 5-HTP, treated with ovalbumin fraction V (OVA), house dust mite (HDM) extract, or IL-4, and examined for allergic lung inflammation and OVA-induced airway responsiveness. To determine whether 5-HTP reduces leukocyte or eosinophil transendothelial migration, endothelial cells were pretreated with 5-HTP, washed and then used in an in vitro transendothelial migration assay under laminar flow. Interestingly, 5-HTP reduced allergic lung inflammation by 70–90% and reduced antigen-induced airway responsiveness without affecting body weight, blood eosinophils, cytokines, or chemokines. 5-HTP reduced allergen-induced transglutaminase 2 (TG2) expression and serotonylation (serotonin conjugation to proteins) in lung endothelial cells. Consistent with the regulation of endothelial serotonylation in vivo, in vitro pretreatment of endothelial cells with 5-HTP reduced TNF-α-induced endothelial cell serotonylation and reduced leukocyte transendothelial migration. Furthermore, eosinophil and leukocyte transendothelial migration was reduced by inhibitors of transglutaminase and by inhibition of endothelial cell serotonin synthesis, suggesting that endothelial cell serotonylation is key for leukocyte transendothelial migration. In summary, 5-HTP supplementation inhibits endothelial serotonylation, leukocyte recruitment, and allergic inflammation. These data identify novel potential targets for intervention in allergy/asthma.

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Zlotorynski, Eytan. "Histone serotonylation boosts neuronal transcription." Nature Reviews Molecular Cell Biology 20, no. 6 (April 3, 2019): 323. http://dx.doi.org/10.1038/s41580-019-0124-4.

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Muma, Nancy A., and Zhen Mi. "Serotonylation and Transamidation of Other Monoamines." ACS Chemical Neuroscience 6, no. 7 (February 5, 2015): 961–69. http://dx.doi.org/10.1021/cn500329r.

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Watts, Stephanie W., Jessica R. C. Priestley, and Janice M. Thompson. "Serotonylation of Vascular Proteins Important to Contraction." PLoS ONE 4, no. 5 (May 25, 2009): e5682. http://dx.doi.org/10.1371/journal.pone.0005682.

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Anastas, Jamie N., and Yang Shi. "Histone Serotonylation: Can the Brain Have “Happy” Chromatin?" Molecular Cell 74, no. 3 (May 2019): 418–20. http://dx.doi.org/10.1016/j.molcel.2019.04.017.

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Lin, Jason Ching-Yao, Chi-Chi Chou, Zhijay Tu, Lun-Fu Yeh, Shang-Chuen Wu, Kay-Hooi Khoo, and Chun-Hung Lin. "Characterization of Protein Serotonylation via Bioorthogonal Labeling and Enrichment." Journal of Proteome Research 13, no. 8 (July 23, 2014): 3523–29. http://dx.doi.org/10.1021/pr5003438.

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Zhao, Shuai, Kelly N. Chuh, Baichao Zhang, Barbara E. Dul, Robert E. Thompson, Lorna A. Farrelly, Xiaohui Liu, et al. "Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout." Proceedings of the National Academy of Sciences 118, no. 6 (February 1, 2021): e2016742118. http://dx.doi.org/10.1073/pnas.2016742118.

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Serotonylation of glutamine 5 on histone H3 (H3Q5ser) was recently identified as a permissive posttranslational modification that coexists with adjacent lysine 4 trimethylation (H3K4me3). While the resulting dual modification, H3K4me3Q5ser, is enriched at regions of active gene expression in serotonergic neurons, the molecular outcome underlying H3K4me3–H3Q5ser crosstalk remains largely unexplored. Herein, we examine the impact of H3Q5ser on the readers, writers, and erasers of H3K4me3. All tested H3K4me3 readers retain binding to the H3K4me3Q5ser dual modification. Of note, the PHD finger of TAF3 favors H3K4me3Q5ser, and this binding preference is dependent on the Q5ser modification regardless of H3K4 methylation states. While the activity of the H3K4 methyltransferase, MLL1, is unaffected by H3Q5ser, the corresponding H3K4me3/2 erasers, KDM5B/C and LSD1, are profoundly inhibited by the presence of the mark. Collectively, this work suggests that adjacent H3Q5ser potentiates H3K4me3 function by either stabilizing H3K4me3 from dynamic turnover or enhancing its physical readout by downstream effectors, thereby potentially providing a mechanism for fine-tuning critical gene expression programs.

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Wang, Han-Ming, Wan-Zhu Liu, Fu-Tian Tang, Hai-Juan Sui, Xing-Jie Zhan, and Hong-Xin Wang. "Cystamine slows but not inverses the progression of monocrotaline-induced pulmonary arterial hypertension in rats." Canadian Journal of Physiology and Pharmacology 96, no. 8 (August 2018): 783–89. http://dx.doi.org/10.1139/cjpp-2017-0720.

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Tissue transglutaminase (TG2) plays an important role in pulmonary arterial hypertension (PAH). Previous research indicate that TG2 and protein serotonylation catalyzed by TG2 are upregulated in PAH. Serotonin transporter inhibitor fluoxetine ameliorates PAH via inhibition of protein serotonylation. It is still unknown whether PAH is inhibited through direct inhibition of TG2. Therefore, the present study aimed to investigate the effects of TG2 inhibitor cystamine on monocrotaline-induced PAH in rats. Rats were treated with monocrotaline (60 mg·kg−1, i.p.) in combination with or without cystamine (20, 40 mg·kg−1·day−1, p.o.). The results showed that compared with monocrotaline alone, combination of monocrotaline with cystamine (40 mg·kg−1·day−1, p.o.) relieved right ventricle hypertrophy, inhibited pulmonary arteriolar remodeling, and downregulated protein expression of TG2, phosphorylated protein kinase B (Akt), and extracellular regulated protein kinase (ERK) at day 21. However, except for TG2 expression, these changes were not significantly inhibited by cystamine at day 35. In addition, cystamine dose-dependently enhanced the survival rate of rats injected with monocrotaline at day 35. The findings suggest that cystamine slows but not reverses monocrotaline-induced PAH in rats, which was largely associated with the inhibition of TG2 protein expression and Akt and ERK activation.

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Soveg, Frank, Hiam Abdala-Valencia, Jackson Campbell, Luisa Morales-Nebreda, Gökhan M. Mutlu, and Joan M. Cook-Mills. "Regulation of allergic lung inflammation by endothelial cell transglutaminase 2." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 6 (September 15, 2015): L573—L583. http://dx.doi.org/10.1152/ajplung.00199.2015.

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Tissue transglutaminase 2 (TG2) is an enzyme with multiple functions, including catalysis of serotonin conjugation to proteins (serotonylation). Previous research indicates that TG2 expression is upregulated in human asthma and in the lung endothelium of ovalbumin (OVA)-challenged mice. It is not known whether endothelial cell TG2 is required for allergic inflammation. Therefore, to determine whether endothelial cell TG2 regulates allergic inflammation, mice with an endothelial cell-specific deletion of TG2 were generated, and these mice were sensitized and challenged in the airways with OVA. Deletion of TG2 in endothelial cells blocked OVA-induced serotonylation in lung endothelial cells, but not lung epithelial cells. Interestingly, deletion of endothelial TG2 reduced allergen-induced increases in respiratory system resistance, number of eosinophils in the bronchoalveolar lavage, and number of eosinophils in the lung tissue. Endothelial cell deletion of TG2 did not alter expression of adhesion molecules, cytokines, or chemokines that regulate leukocyte recruitment, consistent with other studies, demonstrating that deletion of endothelial cell signals does not alter lung cytokines and chemokines during allergic inflammation. Taken together, the data indicate that endothelial cell TG2 is required for allergic inflammation by regulating the recruitment of eosinophils into OVA-challenged lungs. In summary, TG2 functions as a critical signal for allergic lung responses. These data identify potential novel targets for intervention in allergy/asthma.

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Wei, Lin, Rod R. Warburton, Ioana R. Preston, Kari E. Roberts, Suzy A. A. Comhair, Serpil C. Erzurum, Nicholas S. Hill, and Barry L. Fanburg. "Serotonylated fibronectin is elevated in pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 302, no. 12 (June 15, 2012): L1273—L1279. http://dx.doi.org/10.1152/ajplung.00082.2012.

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Serotonin (5-HT) and fibronectin (FN) have been associated with pulmonary hypertension (PH). We previously reported that FN is posttranslationally modified by tissue transglutaminase (TGase) to form serotonylated FN (s-FN) in pulmonary artery smooth muscle cells and that serotonylation stimulates their proliferation and migration, hallmarks of PH. We hypothesized that s-FN and its binding to TGase are elevated in human and experimental PH. To assess this hypothesis, FN isolation and electrophoretic, immunoblotting, and densitometric techniques were used. Mean ratio of serum s-FN to total FN level (s-FN/FN) was elevated in 19 consecutive pulmonary arterial hypertension (PAH) patients compared with 25 controls (0.3 ± 0.18 vs. 0.05 ± 0.07, P < 0.001). s-FN/FN also was increased in lungs of mice and rats with hypoxia-induced PH and in rats with monocrotaline-induced PH. In mice, the increase was detected at 1 wk of hypoxia, preceding the development of PH. Hypoxic rats had elevated serum s-FN/FN. Enhanced binding of TGase to its substrate FN occurred in serum from patients with PAH (mean 0.50 ± 0.51 vs. 0.063 ± 0.11, P = 0.002) and s-FN/FN and TGase-bound FN were highly correlated ( R2 = 0.77). TGase-bound FN also was increased in experimental PH. We conclude that increased serotonylation of FN occurs in human and experimental PH and may provide a biomarker for the disease.

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Zhao, Jie, Wanbiao Chen, Yi Pan, Yinfeng Zhang, Huiying Sun, Han Wang, Fan Yang, et al. "Structural insights into the recognition of histone H3Q5 serotonylation by WDR5." Science Advances 7, no. 25 (June 2021): eabf4291. http://dx.doi.org/10.1126/sciadv.abf4291.

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Serotonylation of histone H3Q5 (H3Q5ser) is a recently identified posttranslational modification of histones that acts as a permissive marker for gene activation in synergy with H3K4me3 during neuronal cell differentiation. However, any proteins that specifically recognize H3Q5ser remain unknown. Here, we found that WDR5 interacts with the N-terminal tail of histone H3 and functions as a “reader” for H3Q5ser. Crystal structures of WDR5 in complex with H3Q5ser and H3K4me3Q5ser peptides revealed that the serotonyl group is accommodated in a shallow surface pocket of WDR5. Experiments in neuroblastoma cells demonstrate that H3K4me3 modification is hampered upon disruption of WDR5-H3Q5ser interaction. WDR5 colocalizes with H3Q5ser in the promoter regions of cancer-promoting genes in neuroblastoma cells, where it promotes gene transcription to induce cell proliferation. Thus, beyond revealing a previously unknown mechanism through which WDR5 reads H3Q5ser to activate transcription, our study suggests that this WDR5-H3Q5ser–mediated epigenetic regulation apparently promotes tumorigenesis.

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Farrelly, Lorna A., Robert E. Thompson, Shuai Zhao, Ashley E. Lepack, Yang Lyu, Natarajan V. Bhanu, Baichao Zhang, et al. "Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3." Nature 567, no. 7749 (March 2019): 535–39. http://dx.doi.org/10.1038/s41586-019-1024-7.

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Paulmann, Nils, Maik Grohmann, Jörg-Peter Voigt, Bettina Bert, Jakob Vowinckel, Michael Bader, Maša Skelin, et al. "Intracellular Serotonin Modulates Insulin Secretion from Pancreatic β-Cells by Protein Serotonylation." PLoS Biology 7, no. 10 (October 27, 2009): e1000229. http://dx.doi.org/10.1371/journal.pbio.1000229.

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Hummerich, René, and Patrick Schloss. "Serotonin—more than a neurotransmitter: transglutaminase-mediated serotonylation of C6 glioma cells and fibronectin." Neurochemistry International 57, no. 1 (August 2010): 67–75. http://dx.doi.org/10.1016/j.neuint.2010.04.020.

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Bode, C., and D. Duerschmied. "The role of serotonin in haemostasis." Hämostaseologie 29, no. 04 (2009): 356–59. http://dx.doi.org/10.1055/s-0037-1617140.

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SummarySerotonin is transported by platelets and released upon activation. This induces constriction of injured blood vessels and enhances platelet aggregation to minimize blood loss. Consequently, serotonin receptor antagonists have been tested for their anti-ischemic potency in atherothrombotic disease. Unfortunately, the results have been contradictory. Recent murine studies found that activation of the platelet serotonin receptor induces shedding of important adhesion molecules. As a consequence, platelets lose their ability to contribute to thrombus formation and may be cleared from the circulation. Serotonin effects on platelets are not only mediated by receptor binding but also by covalently binding effector proteins (serotonylation) in the platelet cytoplasm and on the platelet surface. In conclusion, the effects of serotonin on haemo -stasis are complex and new antithrombotic strategies have to account for this complexity.

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Sheftel, Celeste M., and Laura L. Hernandez. "Serotonin stimulated parathyroid hormone related protein induction in the mammary epithelia by transglutaminase-dependent serotonylation." PLOS ONE 15, no. 10 (October 23, 2020): e0241192. http://dx.doi.org/10.1371/journal.pone.0241192.

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Walther, Diego J., Jens-Uwe Peter, Sandra Winter, Markus Höltje, Nils Paulmann, Maik Grohmann, Jakob Vowinckel, et al. "Serotonylation of Small GTPases Is a Signal Transduction Pathway that Triggers Platelet α-Granule Release." Cell 115, no. 7 (December 2003): 851–62. http://dx.doi.org/10.1016/s0092-8674(03)01014-6.

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Lin, Jason Ching-Yao, Chi-Chi Chou, Shijay Gao, Shang-Chuen Wu, Kay-Hooi Khoo, and Chun-Hung Lin. "An in Vivo Tagging Method Reveals that Ras Undergoes Sustained Activation upon Transglutaminase-Mediated Protein Serotonylation." ChemBioChem 14, no. 7 (April 16, 2013): 813–17. http://dx.doi.org/10.1002/cbic.201300050.

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Maity, Sabyasachi, Kayla Farrell, Shaghayegh Navabpour, Sareesh Naduvil Narayanan, and Timothy J. Jarome. "Epigenetic Mechanisms in Memory and Cognitive Decline Associated with Aging and Alzheimer’s Disease." International Journal of Molecular Sciences 22, no. 22 (November 13, 2021): 12280. http://dx.doi.org/10.3390/ijms222212280.

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Epigenetic mechanisms, which include DNA methylation, a variety of post-translational modifications of histone proteins (acetylation, phosphorylation, methylation, ubiquitination, sumoylation, serotonylation, dopaminylation), chromatin remodeling enzymes, and long non-coding RNAs, are robust regulators of activity-dependent changes in gene transcription. In the brain, many of these epigenetic modifications have been widely implicated in synaptic plasticity and memory formation. Dysregulation of epigenetic mechanisms has been reported in the aged brain and is associated with or contributes to memory decline across the lifespan. Furthermore, alterations in the epigenome have been reported in neurodegenerative disorders, including Alzheimer’s disease. Here, we review the diverse types of epigenetic modifications and their role in activity- and learning-dependent synaptic plasticity. We then discuss how these mechanisms become dysregulated across the lifespan and contribute to memory loss with age and in Alzheimer’s disease. Collectively, the evidence reviewed here strongly supports a role for diverse epigenetic mechanisms in memory formation, aging, and neurodegeneration in the brain.

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Tatsukawa, Hideki, and Kiyotaka Hitomi. "Role of Transglutaminase 2 in Cell Death, Survival, and Fibrosis." Cells 10, no. 7 (July 20, 2021): 1842. http://dx.doi.org/10.3390/cells10071842.

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Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme catalyzing the crosslinking between Gln and Lys residues and involved in various pathophysiological events. Besides this crosslinking activity, TG2 functions as a deamidase, GTPase, isopeptidase, adapter/scaffold, protein disulfide isomerase, and kinase. It also plays a role in the regulation of hypusination and serotonylation. Through these activities, TG2 is involved in cell growth, differentiation, cell death, inflammation, tissue repair, and fibrosis. Depending on the cell type and stimulus, TG2 changes its subcellular localization and biological activity, leading to cell death or survival. In normal unstressed cells, intracellular TG2 exhibits a GTP-bound closed conformation, exerting prosurvival functions. However, upon cell stimulation with Ca2+ or other factors, TG2 adopts a Ca2+-bound open conformation, demonstrating a transamidase activity involved in cell death or survival. These functional discrepancies of TG2 open form might be caused by its multifunctional nature, the existence of splicing variants, the cell type and stimulus, and the genetic backgrounds and variations of the mouse models used. TG2 is also involved in the phagocytosis of dead cells by macrophages and in fibrosis during tissue repair. Here, we summarize and discuss the multifunctional and controversial roles of TG2, focusing on cell death/survival and fibrosis.

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Wang, Han-Ming, Yun Wang, Ming Liu, Yang Bai, Xin-Hua Zhang, Ying-Xian Sun, and Huai-Liang Wang. "Fluoxetine inhibits monocrotaline-induced pulmonary arterial remodeling involved in inhibition of RhoA–Rho kinase and Akt signalling pathways in rats." Canadian Journal of Physiology and Pharmacology 90, no. 11 (November 2012): 1506–15. http://dx.doi.org/10.1139/y2012-108.

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Activation of the small GTPase Ras homolog gene family member A (RhoA) and Rho-associated kinase (ROCK) are important in the pathogenesis of pulmonary arterial hypertension (PAH). Selective serotonin reuptake inhibitors inhibit activation of RhoA and ROCK in vitro, and ameliorate PAH and pulmonary arterial remodeling in vivo. However, little is known about whether the RhoA–ROCK signalling pathway is involved in the treatment of PAH with fluoxetine in vivo. The aim of the present study was to investigate the involvement of the RhoA–ROCK signalling pathway in the protective effect of the selective serotonin reuptake inhibitor fluoxetine against monocrotaline (MCT)-induced pulmonary arterial remodeling. MCT was applied to establish PAH in male Wistar rats. Fluoxetine was administered by gastric gavage once a day for 21 d. The results showed that MCT induced pulmonary arterial remodeling, raised the serotonylation and membrane translocation of RhoA in the lungs, and increased serotonin transporter (5-HTT), RhoA, and ROCK2 expression, and extracellular signal-regulated kinase (ERK) and Akt phosphorylation in the pulmonary arteries and the lungs. Fluoxetine markedly inhibited these MCT-induced changes. The findings suggest that fluoxetine inhibits MCT-induced pulmonary arterial remodeling in rats by inhibition of the RhoA–ROCK and Akt signalling pathways.

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Sedley, Lynda. "Advances in Nutritional Epigenetics—A Fresh Perspective for an Old Idea. Lessons Learned, Limitations, and Future Directions." Epigenetics Insights 13 (January 2020): 251686572098192. http://dx.doi.org/10.1177/2516865720981924.

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Nutritional epigenetics is a rapidly expanding field of research, and the natural modulation of the genome is a non-invasive, sustainable, and personalized alternative to gene-editing for chronic disease management. Genetic differences and epigenetic inflexibility resulting in abnormal gene expression, differential or aberrant methylation patterns account for the vast majority of diseases. The expanding understanding of biological evolution and the environmental influence on epigenetics and natural selection requires relearning of once thought to be well-understood concepts. This research explores the potential for natural modulation by the less understood epigenetic modifications such as ubiquitination, nitrosylation, glycosylation, phosphorylation, and serotonylation concluding that the under-appreciated acetylation and mitochondrial dependant downstream epigenetic post-translational modifications may be the pinnacle of the epigenomic hierarchy, essential for optimal health, including sustainable cellular energy production. With an emphasis on lessons learned, this conceptional exploration provides a fresh perspective on methylation, demonstrating how increases in environmental methane drive an evolutionary down regulation of endogenous methyl groups synthesis and demonstrates how epigenetic mechanisms are cell-specific, making supplementation with methyl cofactors throughout differentiation unpredictable. Interference with the epigenomic hierarchy may result in epigenetic inflexibility, symptom relief and disease concomitantly and may be responsible for the increased incidence of neurological disease such as autism spectrum disorder.

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Drouet, Ludovic, Charlotte Hautefort, Hélène Vitaux, Romain Kania, Jacques Callebert, Alain Stepanian, Virginie Siguret, Michael Eliezer, Nicolas Vodovar, and Jean-Marie Launay. "Plasma Serotonin is Elevated in Adult Patients with Sudden Sensorineural Hearing Loss." Thrombosis and Haemostasis 120, no. 09 (July 27, 2020): 1291–99. http://dx.doi.org/10.1055/s-0040-1713924.

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Abstract Background The roles of thrombophilia and cardiovascular risk factors in sudden sensorineural hearing loss (SSNHL) remain controversial. Cochlear microthrombosis and vasospasm have been hypothesized as possible pathogenic mechanisms of SSNHL. This article investigates the circulating serotonin and homocysteine levels besides thrombophilia screening in patients with idiopathic SSNHL. Methods A total of 133 SSNHL patients and age- and sex-matched controls were investigated (discovery cohort). Measurement included common inherited natural coagulation inhibitors, factor VIII, von Willebrand factor (VWF), antiphospholipid antibodies, homocysteine, and serotonin (whole blood, platelet, and plasma) levels, along with frequent relevant genetic variants. A validation cohort (128 SSNHL patients) was studied for homocysteine and serotonin levels. Results and Conclusion In the discovery cohort, 58.6% of patients exhibited thrombophilia, of which most had a low to moderate titers of antiphospholipid antibodies and high levels of factor VIII/VWF. Twenty-seven patients (20%) had mild-to-moderate hyperhomocysteinemia or were homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Regarding serotonin, SSNHL patients had elevated whole blood levels that remained within the normal range and normal platelet content. However, approximately 90% patients of both cohorts had elevated plasma serotonin. Elevated plasma serotoninemia was accompanied by serotonylation of platelet rhoA protein. This study shows that increased plasma serotonin appears as a biomarker of SSNHL (specificity: ∼96%, sensitivity: ∼90%) and could participate in the pathophysiology of SSNHL.

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Iida, Hiroki, Takashi Onuma, Daiki Nakashima, Daisuke Mizutani, Takamitsu Hori, Kyohei Ueda, Tomoyuki Hioki, et al. "Tramadol regulates the activation of human platelets via Rac but not Rho/Rho-kinase." PLOS ONE 18, no. 1 (January 13, 2023): e0279011. http://dx.doi.org/10.1371/journal.pone.0279011.

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Tramadol is a useful analgesic which acts as a serotonin and noradrenaline reuptake inhibitor in addition to μ-opioid receptor agonist. Cytoplasmic serotonin modulates the small GTPase activity through serotonylation, which is closely related to the human platelet activation. We recently reported that the combination of subthreshold collagen and CXCL12 synergistically activates human platelets. We herein investigated the effect and the mechanism of tramadol on the synergistic effect. Tramadol attenuated the synergistically stimulated platelet aggregation (300 μM of tramadol, 64.3% decrease, p<0.05). Not morphine or reboxetine, but duloxetine, fluvoxamine and sertraline attenuated the synergistic effect of the combination on the platelet aggregation (30 μM of fluvoxamine, 67.3% decrease, p<0.05; 30 μM of sertraline, 67.8% decrease, p<0.05). The geranylgeranyltransferase inhibitor GGTI-286 attenuated the aggregation of synergistically stimulated platelet (50 μM of GGTI-286, 80.8% decrease, p<0.05), in which GTP-binding Rac was increased. The Rac1-GEF interaction inhibitor NSC23766 suppressed the platelet activation and the phosphorylation of p38 MAPK and HSP27 induced by the combination of collagen and CXCL12. Tramadol and fluvoxamine almost completely attenuated the levels of GTP-binding Rac and the phosphorylation of both p38 MAPK and HSP27 stimulated by the combination. Suppression of the platelet aggregation after the duloxetine administration was observed in 2 of 5 patients in pain clinic. These results suggest that tramadol negatively regulates the combination of subthreshold collagen and CXCL12-induced platelet activation via Rac upstream of p38 MAPK.

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"Serotonylation Activates Platelets." Science Signaling 2004, no. 214 (January 6, 2004): tw7. http://dx.doi.org/10.1126/stke.2142004tw7.

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Jiang, Shu-Heng, Ya-Hui Wang, Li-Peng Hu, Xu Wang, Jun Li, Xue-Li Zhang, and Zhi-Gang Zhang. "The physiology, pathology and potential therapeutic application of serotonylation." Journal of Cell Science 134, no. 11 (June 1, 2021). http://dx.doi.org/10.1242/jcs.257337.

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ABSTRACT The classical neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), synthesized from tryptophan, can be produced both centrally and peripherally. Through binding to functionally distinct receptors, serotonin is profoundly implicated in a number of fundamental physiological processes and pathogenic conditions. Recently, serotonin has been found covalently incorporated into proteins, a newly identified post-translational modification termed serotonylation. Transglutaminases (TGMs), especially TGM2, are responsible for catalyzing the transamidation reaction by transferring serotonin to the glutamine residues of target proteins. Small GTPases, extracellular matrix protein fibronectin, cytoskeletal proteins and histones are the most reported substrates for serotonylation, and their functions are triggered by this post-translational modification. This Review highlights the roles of serotonylation in physiology and diseases and provides perspectives for pharmacological interventions to ameliorate serotonylation for disease treatment.

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Sheftel, Celeste, Luma C. Sartori, and Laura L. Hernandez. "SAT-009 SSRI Use in the Peripartum Period Regulates Mammary Gland Parathyroid Hormone Related Protein (PTHrP) by a Serotonylation-Dependent Mechanism." Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.1816.

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Abstract During lactation, a woman experiences a considerable amount of bone loss and recent studies suggest bone deficits persist years postpartum. Furthermore, selective serotonin uptake inhibitors (SSRIs), which are often prescribed to women experiencing peripartum depression, have been linked to osteopenia. Serotonin signaling can increase parathyroid hormone related protein (PTHrP), a bone remodeling protein which liberates calcium for the milk. Additionally, fluoxetine (a common SSRI) results in increased mammary gland serotonin content and PTHrP, and treatment during the peripartal period reduced maternal bone mineral density. One proposed mechanism of serotonin action is by its covalent addition to proteins by transglutaminase (TG2), termed serotonylation. We therefore investigated whether the combination of fluoxetine and lactation can exacerbate maternal bone loss and the underlying mechanism. We hypothesized that SSRI-induced serotonin signaling in the lactating mammary gland increases PTHrP through a serotonylation-dependent mechanism. Treatment of mouse mammary epithelial cells (HC11) with fluoxetine significantly upregulates PTHrP gene expression and the concentration of its downstream effector, cAMP, over control (P < 0.0004). Furthermore, treatment of the HC11 cells with fluoxetine in addition to a TG2 inhibitor, monodansylcadaverine, restores PTHrP mRNA expression to levels observed in the control. Small g-proteins have emerged as a common target protein for serotonylation. Currently, our data suggest that the g-proteins, RhoA and Rab4, are potential serotonylation targets in the mammary gland. Together these data suggest that the molecular process of serotonyation in HC11 cells links serotonin signaling to increased PTHrP expression. Future work is directed at using the cre-lox system to genetically ablate serotonylation using a WAPCre/TG2Flox transgenic mouse to determine whether decreasing serotonylation in vivo in the mammary gland during lactation improves maternal bone mass.

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Bader, Michael. "Serotonylation: Serotonin Signaling and Epigenetics." Frontiers in Molecular Neuroscience 12 (November 21, 2019). http://dx.doi.org/10.3389/fnmol.2019.00288.

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Fu, Lin, and Lingqiang Zhang. "Serotonylation: A novel histone H3 marker." Signal Transduction and Targeted Therapy 4, no. 1 (May 10, 2019). http://dx.doi.org/10.1038/s41392-019-0048-7.

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Lukasak, Bradley J., Michelle M. Mitchener, Lingchun Kong, Barbara E. Dul, Cole D. Lazarus, Aarthi Ramakrishnan, Jizhi Ni, Li Shen, Ian Maze, and Tom W. Muir. "TGM2-mediated histone transglutamination is dictated by steric accessibility." Proceedings of the National Academy of Sciences 119, no. 43 (October 18, 2022). http://dx.doi.org/10.1073/pnas.2208672119.

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Recent studies have identified serotonylation of glutamine-5 on histone H3 (H3Q5ser) as a novel posttranslational modification (PTM) associated with active transcription. While H3Q5ser is known to be installed by tissue transglutaminase 2 (TGM2), the substrate characteristics affecting deposition of the mark, at the level of both chromatin and individual nucleosomes, remain poorly understood. Here, we show that histone serotonylation is excluded from constitutive heterochromatic regions in mammalian cells. Biochemical studies reveal that the formation of higher-order chromatin structures associated with heterochromatin impose a steric barrier that is refractory to TGM2-mediated histone monoaminylation. A series of structure-activity relationship studies, including the use of DNA–barcoded nucleosome libraries, shows that steric hindrance also steers TGM2 activity at the nucleosome level, restricting monoaminylation to accessible sites within histone tails. Collectively, our data indicate that the activity of TGM2 on chromatin is dictated by substrate accessibility rather than by primary sequence determinants or by the existence of preexisting PTMs, as is the case for many other histone-modifying enzymes.

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Liu, Bo, Dong Wang, Erfei Luo, Jiantong Hou, Yong Qiao, Gaoliang Yan, Qingjie Wang, and Chengchun Tang. "Role of TG2-Mediated SERCA2 Serotonylation on Hypoxic Pulmonary Vein Remodeling." Frontiers in Pharmacology 10 (February 11, 2020). http://dx.doi.org/10.3389/fphar.2019.01611.

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Guilluy, Christophe, Saadia Eddahibi, Christian Agard, Laurent Savale, Elie Fadel, Serge Adnot, Pierre Pacaud, and Gervaise Loirand. "Abstract 1633: RhoA and Rho Kinase Activation in Human Pulmonary Hypertension - Role of 5-HT Signaling." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_361-c.

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Background- The complex and multifactorial pathogenesis of pulmonary hypertension (PH) involves constriction, remodeling, and in situ thrombosis of pulmonary vessels. Both serotonin (5-HT) and Rho kinase signaling may contribute to these alterations. Here, we investigated possible links between the 5-HT transporter (5-HTT) and RhoA/Rho kinase pathways, as well as their involvement in the progression of human and experimental PH. Methods and Results- Lungs, platelets, and quiescent cultured pulmonary-artery smooth-muscle cells (PA-SMCs) from patients with idiopathic PH (iPH) were characterized by marked elevations in RhoA and Rho kinase activity and by a strong increase in serotonin binding to RhoA, compared to controls. The 5-HTT inhibitor fluoxetine and the type 2 transglutaminase inhibitor monodansylcadaverin prevented 5-HT-induced RhoA serotonylation and RhoA/Rho kinase activation, as well as 5-HT-induced proliferation of PA-SMCs from iPH patients, that was also inhibited by the Rho kinase inhibitor fasudil. Increased Rho kinase activity, RhoA activation, and RhoA serotonylation were also observed in lungs from SM22–5-HTT+ mice, which overexpress 5-HTT in smooth muscle and spontaneously develop PH. Treatment of SM22–5-HTT+ mice with either fasudil or fluoxetine limited both PH progression and RhoA/Rho kinase activation. Conclusions- RhoA and Rho kinase activities are increased in iPH, as a result of transglutaminase-mediated transamidation of RhoA by 5-HT internalized via 5-HTT. Direct involvement of this pathway in 5-HT-mediated PA-SMC proliferation and platelet activation during PH progression identify RhoA/Rho kinase signaling as a promising target for new treatments against PH.

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Oliver, Kendra H., Heidi E. Hamm, and Ana M. Carneiro. "Abstract 572: Serotonin and Selective Serotonin Reuptake Inhibitors in Platelet Function and RhoA Activation." Arteriosclerosis, Thrombosis, and Vascular Biology 34, suppl_1 (May 2014). http://dx.doi.org/10.1161/atvb.34.suppl_1.572.

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Platelet hyperactivity leads to thrombotic disease, underlying cardiovascular (CV) pathologies including stroke and myocardial infarction. Clinical data suggest that selective serotonin reuptake inhibitors (SSRIs) have hemostatic effects, signifying a potentially novel mechanism to treat CV disease. SSRIs target the serotonin transporter (SERT), which maintains dense-granule serotonin (5HT) in platelets. Serotonin is also a platelet agonist, acting through 5HT2A receptors, yet the full role of 5HT in platelet physiology is not well understood. We hypothesized that SERT KO mice, mimicking chronic SSRI treatment, would exhibit a bleeding phenotype due to reduced platelet function. Consistent with previous reports, we demonstrated that SERT KO mice have decreased whole blood 5HT. There were comparable concentrations of the 5HT metabolite 5HIAA, suggesting that overall synthesis and metabolism of 5HT is unchanged. We next demonstrate that there is a bleeding phenotype in the SERT KO mice through a significantly increased tail-bleed time and increased thrombin time (TT) in whole blood. Additionally, SERT KO mice have reduced platelet retraction, a platelet function attributed to decreased RhoA activation. To determine if sub-chronic SSRI treatment alters platelet function, we treated both wild type and a hyperactive platelet (KI) mice with citalopram in drinking water for 6 days, one day exceeding the turnover rate of platelet production (15mg/kg/day). Activation of RhoA was examined to determine if reduced serotonylation leads to reduced platelet function. Collectively, these data suggest that genetic or pharmacological inhibition of SERT activity could lead to reduced platelet function. These findings may be due to a decrease in intracellular 5HT, as 5HT is still present for 5HT2A activation as determined by the presence of the metabolite. Future experiments will examine the mechanism of SSRI-mediated platelet activity attenuation, which may include reduced serotonylation of important signaling molecules.

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Ye, Di, Huanji Xu, Hongwei Xia, Chenliang Zhang, Qiulin Tang, and Feng Bi. "Targeting SERT promotes tryptophan metabolism: mechanisms and implications in colon cancer treatment." Journal of Experimental & Clinical Cancer Research 40, no. 1 (May 18, 2021). http://dx.doi.org/10.1186/s13046-021-01971-1.

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Abstract Background Serotonin signaling has been associated with tumorigenesis and tumor progression. Targeting the serotonin transporter to block serotonin cellular uptake confers antineoplastic effects in various tumors, including colon cancer. However, the antineoplastic mechanism of serotonin transporter inhibition and serotonin metabolism alterations in the absence of serotonin transporter have not been elucidated, especially in colon cancer, which might limit anti-tumor effects associating with targeting serotonin transporter. Methods The promotion in the uptake and catabolism of extracellular tryptophan and targeting serotonin transporter was detected by using quantitative reverse-transcription polymerase chain reaction, western blotting and liquid chromatography tandem mass spectrometry. Western blotting Immunoprecipitation and immunofluorescence was utilized to research the serotonylation of mTOR by serotonin and serotonin transporter inhibition. The primary mouse model, homograft model and tissue microarry was used to explore the tryptophan pathway in colon cancer. The cell viability assay, western blotting, xenograft and primary colon cancer mouse model were used to identify whether the combination of sertraline and tryptophan restriction had a synergistic effect. Results Targeting serotonin transporter through genetic ablation or pharmacological inhibition in vitro and in vivo induced a compensatory effect by promoting the uptake and catabolism of extracellular tryptophan in colon cancer. Mechanistically, targeting serotonin transporter suppressed mTOR serotonylation, leading to mTOR inactivation and increased tryptophan uptake. In turn, this process promoted serotonin biosynthesis and oncogenic metabolite kynurenine production through enhanced tryptophan catabolism. Tryptophan deprivation, or blocking its uptake by using trametinib, a MEK inhibitor, can sensitize colon cancer to selective serotonin reuptake inhibitors. Conclusions The present study elucidated a novel feedback mechanism involved in the regulation of serotonin homeostasis and suggested innovative strategies for selective serotonin reuptake inhibitors-based treatment of colon cancer.

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Al-Zoairy, Ramona, Michael T. Pedrini, Mohammad Imran Khan, Julia Engl, Alexander Tschoner, Christoph Ebenbichler, Gerhard Gstraunthaler, Karin Salzmann, Rania Bakry, and Andreas Niederwanger. "Serotonin improves glucose metabolism by Serotonylation of the small GTPase Rab4 in L6 skeletal muscle cells." Diabetology & Metabolic Syndrome 9, no. 1 (January 3, 2017). http://dx.doi.org/10.1186/s13098-016-0201-1.

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Voronezhskaya, Elena E. "Maternal Serotonin: Shaping Developmental Patterns and Behavioral Strategy on Progeny in Molluscs." Frontiers in Ecology and Evolution 9 (September 8, 2021). http://dx.doi.org/10.3389/fevo.2021.739787.

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Serotonin is a well-known neurotransmitter and neurohormone regulating mood, sleep, feeding, and learning in high organisms. Serotonin also affects the embryonic events related to neurogenesis and maturation of hormonal systems, the underlying organism adaptation to a changing environment. Such serotonin-based mother-to-embryo signaling is realized via direct interactions in case of internal fertilization and embryonic development inside the mother body. However, the possibility of such signaling is less obvious in organisms with the ancestral type of embryogenesis and embryo development within the egg, outside the mother body. Our data, based on the investigation of freshwater gastropod molluscs (Lymnaea and Helisoma), demonstrated a correlation between seasonal variations of serotonin content within the female reproductive system, and developmental patterns and the behavioral characteristics of progeny. The direct action of serotonin via posttranslational protein modification—serotonylation—during early development, as well as classical receptor-mediated effects, underlies such serotonin-modulated developmental changes. In the present paper, I will shortly overview our results on freshwater molluscs and parallel the experimental data with the living strategy of these species occupying almost all Holarctic regions.

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Redpath, Gregory, and Nikita Deo. "Serotonin: an overlooked regulator of endocytosis and endosomal sorting?" Biology Open 11, no. 1 (January 15, 2022). http://dx.doi.org/10.1242/bio.059057.

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ABSTRACT Serotonin is a neurotransmitter and a hormone that is typically associated with regulating our mood. However, the serotonin transporter and receptors are expressed throughout the body, highlighting the much broader, systemic role of serotonin in regulating human physiology. A substantial body of data strongly implicates serotonin as a fundamental regulator of endocytosis and endocytic sorting. Serotonin has the potential to enhance endocytosis through three distinct mechanisms – serotonin signalling, serotonylation and insertion into the plasma membrane – although the interplay and relationship between these mechanisms has not yet been explored. Endocytosis is central to the cellular response to the extracellular environment, controlling receptor distribution on the plasma membrane to modulate signalling, neurotransmitter release and uptake, circulating protein and lipid cargo uptake, and amino acid internalisation for cell proliferation. Uncovering the range of cellular and physiological circumstances in which serotonin regulates endocytosis is of great interest for our understanding of how serotonin regulates mood, and also the fundamental understanding of endocytosis and its regulation throughout the body. This article has an associated Future Leader to Watch interview with the first author of the paper.

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Rossin, Federica, Fabiola Ciccosanti, Manuela D’Eletto, Luca Occhigrossi, Gian Maria Fimia, and Mauro Piacentini. "Type 2 transglutaminase in the nucleus: the new epigenetic face of a cytoplasmic enzyme." Cellular and Molecular Life Sciences 80, no. 2 (January 25, 2023). http://dx.doi.org/10.1007/s00018-023-04698-8.

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AbstractOne of the major mysteries in science is how it is possible to pack the cellular chromatin with a total length of over 1 m, into a small sphere with a diameter of 5 mm “the nucleus”, and even more difficult to envisage how to make it functional. Although we know that compaction is achieved through the histones, however, the DNA needs to be accessible to the transcription machinery and this is allowed thanks to a variety of very complex epigenetic mechanisms. Either DNA (methylation) or post-translational modifications of histone proteins (acetylation, methylation, ubiquitination and sumoylation) play a crucial role in chromatin remodelling and consequently on gene expression. Recently the serotonylation and dopaminylation of the histone 3, catalyzed by the Transglutaminase type 2 (TG2), has been reported. These novel post-translational modifications catalyzed by a predominantly cytoplasmic enzyme opens a new avenue for future investigations on the enzyme function itself and for the possibility that other biological amines, substrate of TG2, can influence the genome regulation under peculiar cellular conditions. In this review we analyzed the nuclear TG2’s biology by discussing both its post-translational modification of various transcription factors and the implications of its epigenetic new face. Finally, we will focus on the potential impact of these events in human diseases.

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Journal articles on the topic 'Serotonylation'

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