Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells.
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-HT(2B) receptors as key players in controlling the overall 5-HT transport system. In the absence of external 5-HT, 5-HT(2B) receptor coupling to NO production ensures SERT phosphorylation to basal level and maximal 5-HT uptake. In the presence of 5-HT, the 5-HT(2B) receptor-PKC coupling promotes additional phosphorylations of both SERT and Na(+),K(+)-ATPase alpha-subunit, impairing the electrochemical gradient necessary to 5-HT uptake. SERT hyperphosphorylation also affects antidepressant recognition. Finally, such 5-HT(2B) 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
Jean-Marie
JM
Service de Biochimie, Hôpital Lariboisière, Laboratoire de Biologie Cellulaire, Faculté de Pharmacie, Université Paris V, Paris, France. jean-marie.launay@lrb.aphp.fr
Schneider
Benoit
B
Loric
Sylvain
S
Da Prada
Mose
M
Kellermann
Odile
O
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001692:Biological Transport; D002454:Cell Differentiation; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005625:Frontal Lobe / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D011903:Raphe Nuclei / Q000502:physiology; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D000929:Antidepressive Agents, Tricyclic; D012333:RNA, Messenger; D044403:Receptor, Serotonin, 5-HT2B; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin