Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels

Abstract

The serotonin transporter (SERT) on platelets is a primary mechanism for serotonin (5HT) uptake from the blood plasma. Alteration in plasma 5HT level is associated with a number of cardiovascular diseases and disorders. Therefore, the regulation of the transporter's activity represents a key mechanism to stabilize the concentration of plasma 5HT. There is a biphasic relationship between plasma 5HT elevation, loss of surface SERT, and depletion of platelet 5HT. Specifically, in platelets, plasma membrane SERT levels and platelet 5HT uptake initially rise as plasma 5HT levels are increased but then fall below normal as the plasma 5HT level continues to rise. Therefore, we propose that elevated plasma 5HT limits its own uptake in platelets by down-regulating SERT as well as modifying the characteristics of SERT partners in the membrane trafficking pathway. This review will summarize current findings regarding the biochemical mechanisms by which elevated 5HT downregulates the expression of SERT on the platelet membrane. Intriguing aspects of this regulation include the intracellular interplay of SERT with the small G protein Rab4 and the concerted 5HT-mediated phosphorylation of vimentin.

Figure 1

The role of 5HT in platelet function. SERT (dark blue elongated hexagons) within the plasma membrane (light blue line) transports 5HT, which is a signal for platelet activation, from the plasma into the platelet cytoplasm. 5HT is stored within the platelet in dense granules; α-granules store proagulant molecules. Both types of granules can release their contents into the plasma under appropriate platelet stimulation. The internalization and recycling of SERT through platelet trafficking machinery provides a means of regulating 5HT uptake. (See text for details.)

Figure 2

SERT integration into the platelet plasma membrane. Twelve intramembrane domains are predicted for SERT. Sites of glycosylation are indicated at extracellular asparagine residues. The cytoplasmic C-terminal domain contains important regulatory sequences. The SITPET hexapeptide (red residues) is key to SERT trafficking and regulation, putatively providing sites for sequential phosphorylation and interaction with cytoskeletal elements (e.g., vimentin). Residues indicated in green have been implicated in the binding of Rab 4. (See text for details.)

Figure 3

SERT-mediated 5HT uptake: reciprocal regulation of plasma 5HT levels and SERT activity in the platelet plasma membrane. Upon elevation of 5HT concentration (yellow squares) in the plasma (upper right arrow), the uptake rate of 5HT increases, as trafficking vesicles (green circles; see [A] and [B]) deliver SERT (blue geometries) to the platelet surface. The rise in cytoplasmic 5HT [B] promotes the transamination of Rab4 (not schematized), thereby activating Rab4 and promoting its association with SERT; the Rab4–SERT interaction prevents the trafficking of SERT to the plasma membrane [C]. The rise in cytoplasmic 5HT also promotes exocytosis of dense granules (purple circles) and α-granules (green ovals), the latter of which contain procoagulants (hexagons). The internalization of SERT is also promoted as 5HT activates PAK, which phosphorylates vimentin (see [C] and [D]), causing its association with SERT. The indicated roles of Rab4 and vimentin culminate in the reduced surface expression of SERT, which delimits further intake of 5HT, restoring cytoplasmic levels to their initial values (see [D] and [A]). (See text for details.)