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J. Biol. Chem., Vol. 281, Issue 39, 28901-28909, September 29, 2006

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Subcellular Redistribution of the Serotonin Transporter by Secretory Carrier Membrane Protein 2^*

Heidi Kaastrup Müller^¶, Ove Wiborg^¶, and Jana Haase¹

From the School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland, Trinity College Dublin 2, Ireland, and the ^¶Center for Basic Psychiatric Research, Århus Psychiatric University Hospital, 8240 Risskov, Denmark

The serotonin transporter (SERT) belongs to the SLC6 family of sodium- and chloride-dependent neurotransmitter transporters responsible for uptake of amino acids and biogenic amines from extracellular spaces. Their activities and subcellular distributions are regulated by various cellular mechanisms, including interactions with other proteins. Using the yeast two-hybrid approach we screened a human brain cDNA library and identified secretory carrier membrane protein 2 (SCAMP2) as a novel SERT-interacting protein. GST-pulldown assays confirmed the physical interaction between SCAMP2 and the N-terminal domain of SERT. In addition, SERT was found to form a complex with SCAMP2 as demonstrated by co-immunoprecipitation from a heterologous expression system and from rat brain homogenate. Co-expression of SERT and SCAMP2 in mammalian cells results in the subcellular redistribution of SERT with a decrease in cell surface SERT and a concomitant reduction in 5-HT uptake activity. Using confocal microscopy we show that in neuronal cells endogenous SERT co-localizes with SCAMP2 in discrete structures also containing the lipid raft marker flotillin-1 and the SNARE protein syntaxin 1A. In contrast, SERT immunoreactivity is clearly segregated from transferrin receptor-containing endosomes. A single amino acid mutation, cysteine-201 to alanine, within the conserved cytoplasmic E peptide of SCAMP2, abolished SCAMP2-mediated down-regulation of SERT, although this mutation had no effect on the physical interaction between SERT and SCAMP2. Taken together, our results suggest that SCAMP2 plays an important role in the regulation of the subcellular distribution of SERT.

Received for publication, March 27, 2006 , and in revised form, June 30, 2006.

^* This research was funded in part by the Enterprise Ireland Basic Research Grant No. SC/2003/0478 (to J. H.), as well as grants from the Augustinus Foundation, the Beckett Foundation, Direktør Jacob Madsen and hustru Olga Madsens Foundation, and the Aase and Ejnar Danielsens Foundation (to H. K. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Tel.: 353-1-716-6754; Fax: 353-1-2837211; E-mail: jana.haase{at}ucd.ie.

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