| First Author | Oliver KH | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 38 | Pages | 20210-9 |
| PubMed ID | 27422820 | Mgi Jnum | J:237055 |
| Mgi Id | MGI:5810820 | Doi | 10.1074/jbc.M116.736983 |
| Citation | Oliver KH, et al. (2016) Loss of Serotonin Transporter Function Alters ADP-mediated Glycoprotein alphaIIbbeta3 Activation through Dysregulation of the 5-HT2A Receptor. J Biol Chem 291(38):20210-9 |
| abstractText | 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 alphaIIbbeta3 activation upon stimulation with thrombin, ADP-mediated alphaIIbbeta3 activation is reduced in SERT(-/-) platelets. Additionally, synergistic potentiation of alphaIIbbeta3 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 alphaIIbbeta3 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 alphaIIbbeta3 by 5-HT and ADP. These results highlight an antiplatelet strategy centered on blocking or desensitizing 5-HT2AR to attenuate ADP-mediated alphaIIbbeta3 activation. |
