Cited by 180Platelet Disorders and TreatmentsCell Adhesion Molecules ResearchBlood Coagulation and Thrombosis Mechanisms

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Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans

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Carneiro, Ana Marin D., Cook, Edwin H., Murphy, Dennis L., Blakely, Randy D.·2008·Journal of Clinical Investigation

DOI 10.1172/jci33374PMC PMC2260909

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Abstract

The essential contribution of the antidepressant-sensitive serotonin (5-HT) transporter SERT (which is encoded by the SLC6A4 gene) to platelet 5-HT stores suggests an important role of this transporter in platelet function. Here, using SERT-deficient mice, we have established a role for constitutive SERT expression in efficient ADP- and thrombin-triggered platelet aggregation. Additionally, using pharmacological blockers of SERT and the vesicular monoamine transporter (VMAT), we have identified a role for ongoing 5-HT release and SERT activity in efficient human platelet aggregation. We have also demonstrated that fibrinogen, an activator of integrin alphaIIbbeta3, enhances SERT activity in human platelets and that integrin alphaIIbbeta3 interacts directly with the C terminus of SERT. Consistent with these findings, knockout mice lacking integrin beta3 displayed diminished platelet SERT activity. Conversely, HEK293 cells engineered to express human SERT and an activated form of integrin beta3 exhibited enhanced SERT function that coincided with elevated SERT surface expression. Our results support an unsuspected role of alphaIIbbeta3/SERT associations as well as alphaIIbbeta3 activation in control of SERT activity in vivo that may have broad implications for hyperserotonemia, cardiovascular disorders, and autism.

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Authors: Carneiro, A. M. D., Cook, E. H., Murphy, D. L., & Blakely, R. D.
Affiliations: Vanderbilt University (US)
University of Illinois Chicago (US)
National Institutes of Health (US)
Corresponding author: Blakely, Randy D.
ORCID: Carneiro, Ana Marin D.
Cook, Edwin H.
Blakely, Randy D.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2008-04-01
Volume: 118
Issue: 4
Pages: 1544-1552
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci33374
PMC: PMC2260909
OpenAlex: W2144374554
Cited by: 180
References: 50
Citations by year: 2026: 4 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 10 · 2020: 3 · 2019: 13 · 2018: 10 · 2017: 14 · 2016: 9 · 2015: 9 · 2014: 14 · 2013: 13 · 2012: 14
FWCI: 9.36
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Alliance for Research on Schizophrenia and Depression
National Institutes of Health
National Institute of Mental Health (P50MH078028, MH078028, NIMH P50)
National Institute on Drug Abuse (R01DA007390, DA007390)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (U19-HD 35482, U19HD035482)
Topics: Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Keywords: serotonin transporter, integrin αIIbβ3, platelet aggregation, serotonin release, vesicular monoamine transporter, fibrinogen, ADP-induced aggregation, thrombin-induced aggregation, hyperserotonemia, autism spectrum disorder, cardiovascular disease
MeSH terms: Alleles, Animals, Biological Transport, Blood Platelets, Cell Line, Cell Membrane, Humans, Platelet Aggregation, Protein Binding, Serotonin, Mice, Knockout, Platelet Glycoprotein GPIIb-IIIa Complex, MAP Kinase Signaling System, p38 Mitogen-Activated Protein Kinases, Serotonin Plasma Membrane Transport Proteins, Mice, Protein Phosphatase 1, Protein Phosphatase 2

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Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans

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