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Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2006 Sep; Vol. 20 (11), pp. 1843-54. - Publication Year :
- 2006
-
Abstract
- 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.
- Subjects :
- Animals
Biological Transport
Cell Differentiation
Cell Membrane drug effects
Cell Membrane physiology
Cells, Cultured
Male
Mice
Mice, Inbred BALB C
Neurons cytology
Neurons drug effects
Phosphorylation
RNA, Messenger genetics
Raphe Nuclei physiology
Receptor, Serotonin, 5-HT2B drug effects
Receptor, Serotonin, 5-HT2B genetics
Serotonin metabolism
Serotonin Plasma Membrane Transport Proteins genetics
Signal Transduction
Antidepressive Agents, Tricyclic pharmacology
Frontal Lobe physiology
Neurons physiology
Receptor, Serotonin, 5-HT2B physiology
Serotonin physiology
Serotonin Plasma Membrane Transport Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 20
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 16940156
- Full Text :
- https://doi.org/10.1096/fj.06-5724com