Molecular Mechanisms of SERT in Platelets: Regulation of Plasma Serotonin Levels

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.)