PMID:18227069

Citation	Ahmed, BA, Jeffus, BC, Bukhari, SI, Harney, JT, Unal, R, Lupashin, VV, van der Sluijs, P and Kilic, F (2008) Serotonin transamidates Rab4 and facilitates its binding to the C terminus of serotonin transporter. J. Biol. Chem. 283:9388-98
Abstract	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, Rab4-GTP. Although investigating the mechanism by which elevated plasma 5HT level down-regulates the density of SERT molecules 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 Rab4-GTP 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.
Links	PubMed Online version:10.1074/jbc.M706367200
Keywords	Animals; Blood Platelets/cytology; Blood Platelets/metabolism; CHO Cells; Cell Membrane/metabolism; Cricetinae; Cricetulus; Cytoplasm/metabolism; Down-Regulation/drug effects; Down-Regulation/physiology; Guanosine Triphosphate/genetics; HeLa Cells; Humans; Protein Processing, Post-Translational/drug effects; Protein Processing, Post-Translational/physiology; Protein Structure, Tertiary/physiology; Protein Transport/physiology; Serotonin/metabolism; Serotonin/pharmacology; Serotonin Plasma Membrane Transport Proteins/genetics; Serotonin Plasma Membrane Transport Proteins/metabolism; rab4 GTP-Binding Proteins/genetics; rab4 GTP-Binding Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:SC6A4	involved_in	GO:0051610: serotonin uptake	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:SC6A4	enables	GO:0017137: Rab GTPase binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P20338	F		Seeded From UniProt	complete
HUMAN:SC6A4	part_of	GO:0012505: endomembrane system	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:SC6A4	part_of	GO:0005886: plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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