Interactions between integrin alphaIIbbeta3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans.
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.
Carneiro
Ana Marin D
AM
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-8548, USA.
Cook
Edwin H
EH
Murphy
Dennis L
DL
Blakely
Randy D
RD
D000483:Alleles; D000818:Animals; D001692:Biological Transport; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D048051:p38 Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2