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* Service de Biochimie, IFR 139, Hôpital Lariboisière and Laboratoire de Biologie Cellulaire, EA3621, Faculté de Pharmacie, Université Paris V, Paris, France;
Différenciation Cellulaire et Prions, CNRS UPR 1983, Institut André Lwoff, Villejuif, and Institut Pasteur, Département de Biologie Cellulaire et Infections, Paris, France; and
Pharma Research Department, Hoffmann-La Roche A.G., Basel, Switzerland
1Correspondence: Service de Biochimie, Hôpital Lariboisière, 75475 Paris Cedex 10, France. E-mail: jean-marie.launay{at}lrb.aphp.fr
The plasma membrane 5-HT transporter (SERT) is the major protagonist in regulating extracellular 5-HT concentration and constitutes the target of drugs used to treat a host of metabolic and psychiatric disorders. The exact mechanisms sustaining SERT function still remain elusive. The present work exploits the properties of the 1C11 neuroectodermal progenitor, which acquires, upon 4 days of differentiation, a functional SERT within an integrated serotonergic phenotype to investigate regulatory mechanisms involved in SERT onset and functions. We show that poly(A) addition precedes SERT mRNA translation on day 2 of the serotonergic program. The newly translated transporter molecules immediately bind cocaine. Day 4 must be awaited to monitor antidepressant recognition and 5-HT uptake. Because external 5-HT reduces both 5-HT transport and SERT antidepressant binding, we identify 5-HT2B receptors as key players in controlling the overall 5-HT transport system. In the absence of external 5-HT, 5-HT2B receptor coupling to NO production ensures SERT phosphorylation to basal level and maximal 5-HT uptake. In the presence of 5-HT, the 5-HT2B receptor-PKC coupling promotes additional phosphorylations of both SERT and Na+,K+-ATPase 
-subunit, impairing the electrochemical gradient necessary to 5-HT uptake. SERT hyperphosphorylation also affects antidepressant recognition. Finally, such 5-HT2B receptor-mediated control of SERT activity operates in primary neurons from raphe nuclei. Altogether, our data shed new light on the 5-HT-driven post-translational modifications involved in the control of SERT activity.—Launay, J-M., Schneider, B., Loric, S., Da Prada, M., Kellermann, O. Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells.
Key Words: SERT • neuronal differentiation • transporter(s)
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