ArticleThe Journal of biological chemistry2016
Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein αIIbβ3 Activation through Dysregulation of the 5-HT2A Receptor.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 27 citations in OpenAlex.
- Serotonin transporter deficiency, but not absence of platelet serotonin, impairs thrombus formation in a model of deep vein thrombosis.Research and practice in thrombosis and haemostasis · 2025Article
- Serotonin and the serotonin transporter in the adrenal gland.Vitamins and hormones · 2024Review
- Endophenotype trait domains for advancing gene discovery in autism spectrum disorder.Journal of neurodevelopmental disorders · 2023Review
- Serotonin sensing by microglia conditions the proper development of neuronal circuits and of social and adaptive skills.Molecular psychiatry · 2023Article
- Article
- Genetic deletion ofJournal of psychopharmacology (Oxford, England) · 2020Article
- Use of serotonin reuptake inhibitors is not associated with increased bleeding after CABG.General thoracic and cardiovascular surgery · 2020Article
- Depression and Cardiovascular Disease: The Viewpoint of Platelets.International journal of molecular sciences · 2020Review
- Whole Blood Serotonin Levels and Platelet 5-HTJournal of autism and developmental disorders · 2019Article
- Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis.Nature reviews. Rheumatology · 2019Review
- Adrenal serotonin derives from accumulation by the antidepressant-sensitive serotonin transporter.Pharmacological research · 2019Article
- Citalopram inhibits platelet function independently of SERT-mediated 5-HT transport.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Reduced platelet aggregation and a mild bleeding phenotype have been observed in patients chronically taking selective serotonin reuptake inhibitors (SSRIs). However, it remains unclear how SSRIs, which inhibit the plasma membrane serotonin transporter (SERT), modulate hemostasis. Here, we examine how sustained inhibition of SERT activity alters serotonergic signaling and influences platelet activation and hemostasis. Pharmaceutical blockade (citalopram dosing) or genetic ablation (SERT(-/-)) of SERT function in vivo led to reduced serotonin (5-hydroxytryptamine (5-HT)) blood levels that paralleled a mild bleeding phenotype in mice. Transfusion of wild-type platelets to SERT(-/-) mice normalized bleeding times to wild-type levels, suggesting that loss of SERTs causes a deficiency in platelet activation. Although SERT(-/-) platelets displayed no difference in P-selectin or αIIbβ3 activation upon stimulation with thrombin, ADP-mediated αIIbβ3 activation is reduced in SERT(-/-) platelets. Additionally, synergistic potentiation of αIIbβ3 activation by ADP and 5-HT is lost in SERT(-/-) platelets. Acute treatment of wild-type platelets with 5-HT2A receptor (5-HT2AR) antagonists or SSRIs revealed that functional 5-HT2ARs, not SERTs, are necessary for the synergistic activation of αIIbβ3 by dual 5-HT/ADP stimulation. Pharmacological studies using radiolabeled guanosine 5'-3-O-([(35)S]thio)triphosphate and [(3)H]ketanserin revealed that platelets isolated from SERT(-/-) or citalopram-treated mice have reduced activation of G-proteins coupled to 5-HT2ARs and receptor surface expression. Taken together, these data demonstrate that sustained SERT loss of function reduces 5-HT2AR surface expression that is critical for the synergistic activation of αIIbβ3 by 5-HT and ADP. These results highlight an antiplatelet strategy centered on blocking or desensitizing 5-HT2AR to attenuate ADP-mediated αIIbβ3 activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.