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 ADPand 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.

Enhanced activity of human serotonin transporter variants associated with autism

“…NOS1 proteins have recently been found to associate with SERTs (Chanrion et al 2007), and we have shown that NOS activation is a critical step between A3 adenosine receptor activation and SERT stimulation; further focus on NOS1 structural and regulatory pathways seem worthy of investment for additional insights into autism risk. Finally, we recently documented the physical association and regulation of SERT by integrin b3 (Carneiro et al 2008). Integrin b3 has been associated with whole blood hyperserotonaemia (Weiss et al 2004) and with autism ( Weiss et al 2006).…”

Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes

“…14 Also the Leu33Pro ITGB3 SNP (rs5918) modulates SLC6A4 trafficking and transport activity. 19 Finally, several recently published studies have described significant SLC6A4 and ITGB3 interactions for both autism risk and 5-HT blood levels, with a male-specific effect. 10,[14][15][16][17]20 Despite these positive findings, several inconsistencies complicate their interpretation, possibly because of clinical and genetic heterogeneity in ASD.…”

Evidencia de asociación entre el gen SLC6A4 y efectos epistáticos con variantes en HTR2A en la etiología del autismo en población antioqueña

“…En el 2008, Carneiro, et al, encontraron una evidencia funcional de la interacción entre las proteínas codificadas por los genes ITGB3 (αIIbβ3) y SLC6A4 (SERT) (89).…”

“…Estos resultados señalan que se requiere una adecuada expresión o señalización de αIIbβ3 para la función normal de la SERT (89). Las plaquetas que portan el polimorfismo Pro33 en ITGB3, cercano al polimorfismo evaluado en este trabajo, Leu59Pro, mostraron un incremento en la activación αIIbβ3, por la unión a fibrinógeno.…”

“…Las plaquetas que portan el polimorfismo Pro33 en ITGB3, cercano al polimorfismo evaluado en este trabajo, Leu59Pro, mostraron un incremento en la activación αIIbβ3, por la unión a fibrinógeno. Se observó un incremento del 260 % en la actividad de captura de la proteína SERT por la presencia del alelo Pro33 en ITGB3 en relación con el homocigoto para Leu33 (89).…”