Serotonin transporter (SERT) on the surface membrane of platelets is the major mechanism for serotonin (5HT) uptake from plasma to platelet. Following uptake, 5HT is removed from the cytoplasm by the vesicular monoamine transporter (VMAT) and stored in dense granules which are released during platelet aggregation and other intravascular events. Today, the involvement of 5HT in platelet aggregation is accepted. However, very little is known regarding with the mechanisms by which 5HT mediates the aggregation process.
The 5HT uptake capacity of platelets is dependent on the number of SERT molecules on the plasma membrane. Our in vivo and in vitro studies confirmed a dynamic relationship between an elevation in plasma 5HT and the loss of SERT in the plasma membrane (PM) of platelets. Specifically, the density of SERT on the plasma membrane and 5HT uptake by SERT initially rise as plasma 5HT levels are increased and then fall below normal as the plasma 5HT level continues to rise. Thus, a high level of 5HT in plasma appears to limit its own uptake in platelets by down-regulating platelet SERT expression, resulting in a loss of intracellular 5HT but increased plasma concentration.
To define the biochemical mechanisms by which elevated 5HT down-regulates the expression of SERT on the platelet membrane and to study the impact of this event in platelet biology, we established a mouse model in which plasma 5HT was chronically elevated by osmotic mini-pump. For the first time using an in vivo model system, we show that platelets isolated from the 5HT-infused mice appear to aggregate more readily. However, the rates and the degree of the aggregation of these platelets are significantly altered by the inhibitors of SERT, dense granule-specific VMAT, or platelet-specific 5HT receptor. Our data suggest that 5HT-mediated platelet aggregation is a two-step process, which is initiated by SERT and amplified by 5HT-2A receptor to elevate the free cytoplasmic 5HT. These findings provide new mechanistic insight into the physiology and pathophysiology of platelets under elevated blood 5HT.
|Commitee:||Marsh, James D., Raney, Kevin D., Rusch, Nancy J., Straub, Karl D., Ware, Jerry|
|School:||University of Arkansas for Medical Sciences|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 73/10(E), Dissertation Abstracts International|
|Keywords:||Cardiovascular disease, Platelet activation, Serotonin|
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