Abstract
Citalopram, a selective serotonin reuptake inhibitor (SSRI), inhibits platelet function in vitro. We have previously shown that this action is independent of citalopram’s ability to block serotonin uptake by the serotonin transporter and must therefore be mediated via distinct pharmacological mechanisms. We now report evidence for two novel and putative mechanisms of citalopram-induced platelet inhibition. Firstly, in platelets, citalopram blocked U46619-induced Rap1 activation and subsequent platelet aggregation, but failed to inhibit U46619-induced increases in cytosolic Ca2+. Similarly, in neutrophils, citalopram inhibited Rap1 activation and downstream functions but failed to block PAF-induced Ca2+ mobilisation. In a cell-free system, citalopram also reduced CalDAG-GEFI-mediated nucleotide exchange on Rap1B. Secondly, the binding of anti-GPVI antibodies to resting platelets was inhibited by citalopram. Furthermore, citalopram-induced inhibition of GPVI-mediated platelet aggregation was instantaneous, reversible and displayed competitive characteristics, suggesting that these effects were not caused by a reduction in GPVI surface expression, but by simple competitive binding. In conclusion, we propose two novel, putative and distinct inhibitory mechanisms of action for citalopram: (1) inhibition of CalDAG-GEFI/Rap1 signalling, and (2) competitive antagonism of GPVI in platelets. These findings may aid in the development of novel inhibitors of CalDAG-GEFI/Rap1-dependent nucleotide exchange and novel GPVI antagonists.
Highlights
Citalopram, a selective serotonin reuptake inhibitor (SSRI), is widely used as an antidepressant[1]
These just sub-maximal concentrations of CRPXL and U46619 were selected based on prior pilot experiments (Supplementary Fig. S1)
We have previously shown that citalopram-induced inhibition of platelet function is not caused by blockade of serotonin transporter (SERT)-dependent 5-HT uptake into platelets[10]
Summary
Citalopram, a selective serotonin reuptake inhibitor (SSRI), is widely used as an antidepressant[1]. Citalopram inhibits platelet SERT, and platelet aggregation, adhesion, thromboxane A2 (TxA2) synthesis and dense granule release[8,9,10,11,12] This functional inhibition is not caused by blockade of 5-HT uptake and must be mediated by distinct pharmacological mechanisms of action[10]. Citalopram is a more potent inhibitor of collagen[10], which activates platelets predominantly via glycoprotein VI (GPVI), than U46619, a thromboxane prostanoid (TP) receptor agonist, suggesting differential mechanisms of action. GPVI inhibition would not account for citalopram’s effect on U46619-induced responses Both GPVI and TP receptor activation raise cytosolic calcium concentrations ([Ca2+]cyt), a shared signalling pathway for collagen, TxA2, and many other platelet agonists. Our data reveal two novel, putative inhibitory mechanisms of action for citalopram
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
