Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans
Ana Marin D. Carneiro, … , Dennis L. Murphy, Randy D. Blakely
Ana Marin D. Carneiro, … , Dennis L. Murphy, Randy D. Blakely
Published March 3, 2008
Citation Information: J Clin Invest. 2008;118(4):1544-1552. https://doi.org/10.1172/JCI33374.
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Research Article Hematology

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

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 αIIbβ3, enhances SERT activity in human platelets and that integrin αIIbβ3 interacts directly with the C terminus of SERT. Consistent with these findings, knockout mice lacking integrin β3 displayed diminished platelet SERT activity. Conversely, HEK293 cells engineered to express human SERT and an activated form of integrin β3 exhibited enhanced SERT function that coincided with elevated SERT surface expression. Our results support an unsuspected role of αIIbβ3/SERT associations as well as αIIbβ3 activation in control of SERT activity in vivo that may have broad implications for hyperserotonemia, cardiovascular disorders, and autism.

Authors

Ana Marin D. Carneiro, Edwin H. Cook, Dennis L. Murphy, Randy D. Blakely

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Figure 6

Model for αIIbβ3 regulation of SERT function and 5-HT signaling in platelets.

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Model for αIIbβ3 regulation of SERT function and 5-HT signaling in plate...
(A) SERT-KO platelets lack intracellular 5-HT stores that can be released upon integrin activation. This absence of granule 5-HT leads to diminished aggregation induced by ADP. (B) Leu33 platelets exhibit low basal 5-HT uptake activity, sufficient to maintain granule stores of 5-HT. Binding of immobilized fibrinogen to αIIbβ3 leads to changes in SERT uptake activity that can enhance granule secretion through serotonylation of small Rho GTPases. The depletion of granule stores by reserpine or inhibition of SERT uptake activity by citalopram diminishes platelet aggregation. (C) Integrin β3 Pro33 isoform enhances SERT uptake activity and membrane expression, leading to elevated platelet 5-HT levels. The molecular mechanism for the Pro33 cells involve enhanced PP1 and basal p38 MAPK phosphorylation levels and consequent altered PP2A pathways.