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Serotonin transport and serotonin transporter‐mediated antidepressant recognition are controlled by 5‐HT 2B receptor signaling in serotonergic neuronal cells
Author(s) -
Lamiay JeanMarie,
Schneider Benoit,
Loric Sylvain,
Prada Mose Da,
Kellermann Odile
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-5724com
Subject(s) - serotonergic , serotonin transporter , serotonin plasma membrane transport proteins , serotonin , antidepressant , dorsal raphe nucleus , 5 ht receptor , biology , receptor , microbiology and biotechnology , chemistry , neuroscience , endocrinology , medicine , biochemistry , hippocampus
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 α‐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, J‐M., Schneider, B., Loric, S., Da Prada, M., Kellermann, O. Serotonin transport and serotonin transporter‐mediated antidepressant recognition are controlled by 5‐HT 2B receptor signaling in serotonergic neuronal cells. FASEB J . 20, 1843–1854 (2006)