Serotonin transamidates Rab4 and facilitates its binding to the C terminus of serotonin transporter (Publication with Expression of Concern. See vol. 294, pg. 5209, 2019) (Withdrawn Publication. See vol. 294, pg. 9658, 2019)

The serotonin transporter (SERT) on the plasma membrane is the major mechanism for the clearance of plasma serotonin (5-hydroxytryptamine (5HT)). The uptake rates of cells depend on the density of SERT molecules on the plasma membrane. Interestingly, the number of SERT molecules on the platelet surface is down-regulated when plasma 5HT ([5HT] ex) is elevated. It is well reported that stimulation of cells with high [5HT] ex induces transamidation of a small GTPase, Rab4. Modification with 5HT stabilizes Rab4 in its active, GTP-bound form, Rab4GTP. Although investigating the mechanism by which elevated plasma5HTlevel down-regulates the density ofSERTmolecules on the plasma membrane, we studied Rab4 and SERT in heterologous and platelet expression systems. Our data demonstrate that, in response to elevated [5HT] ex, Rab4-GTP co-localizes with and binds to SERT. The association of SERT with Rab4GTP depends on: (i) 5HT modification and (ii) the GTP-binding ability of Rab4. Their association retains transporter molecules intracellularly. Furthermore, we mapped the Rab4-SERT association domain to amino acids 616-624 in the cytoplasmic tail of SERT. This finding provides an explanation for the role of the C terminus in the localization and trafficking of SERT via Rab4 in a plasma 5HT-dependent manner. Therefore, we propose that elevated [5HT](ex) "paralyzes" the translocation of SERT from intracellular locations to the plasma membrane by controlling transamidation and Rab4-GTP formation.