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PMID:16940156
| Citation |
Launay, JM, Schneider, B, Loric, S, Da Prada, M and Kellermann, O (2006) Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells. FASEB J. 20:1843-54 |
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| 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. |
| Links |
PubMed Online version:10.1096/fj.06-5724com |
| Keywords |
Animals; Antidepressive Agents, Tricyclic/pharmacology; Biological Transport; Cell Differentiation; Cell Membrane/drug effects; Cell Membrane/physiology; Cells, Cultured; Frontal Lobe/physiology; Male; Mice; Mice, Inbred BALB C; Neurons/cytology; Neurons/drug effects; Neurons/physiology; Phosphorylation; RNA, Messenger/genetics; Raphe Nuclei/physiology; Receptor, Serotonin, 5-HT2B/drug effects; Receptor, Serotonin, 5-HT2B/genetics; Receptor, Serotonin, 5-HT2B/physiology; Serotonin/metabolism; Serotonin/physiology; Serotonin Plasma Membrane Transport Proteins/genetics; Serotonin Plasma Membrane Transport Proteins/physiology; Signal Transduction |
| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0008144: drug binding |
ECO:0000314: |
F |
Figure 3 and Figure 6 show such activity. |
complete | ||||
See also
References
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