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Journal Article

Modulation of Ligand-Gated Ion Channels as a Novel Pharmacological Principle

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons80461

Nothdurfter,  C.
Rainer Rupprecht (Max-Planck Fellow), Max Planck Institute of Psychiatry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons80547

Tanasic,  S.
Rainer Rupprecht (Max-Planck Fellow), Max Planck Institute of Psychiatry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons80484

Rammes,  G.
AG Eder, Matthias, Florian Holsboer (Direktor), Max Planck Institute of Psychiatry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons80504

Rupprecht,  R.
Rainer Rupprecht (Max-Planck Fellow), Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Nothdurfter, C., Tanasic, S., Rammes, G., & Rupprecht, R. (2011). Modulation of Ligand-Gated Ion Channels as a Novel Pharmacological Principle. Pharmacopsychiatry, 44(Suppl. 1), S27-S34.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-8EB0-6
Abstract
The present study investigated the functional antagonism of different antidepressants on 5-HT3 receptor function and the role of lipid rafts for these modulatory effects. Electrophysiological recordings of 5-HT evoked cation currents were recorded with N1E-115 and HEK-5-HT3A cells and hippocampal neurons. The characterization of the antagonism of antidepressants was made by the displacement of [H-3]GR65630 binding. For membrane fractionation, sucrose density gradient centrifugation was used. Gradient fractions were assayed for antidepressant concentrations by HPLC; 5-HT3 receptor membrane distribution was determined by Western blot. Colocalization experiments were performed by means of immunocytochemistry. Most antidepressants acted as non-competitive antagonists at the 5-HT3 receptor. Moreover, some of these compounds were enriched within lipid rafts. Cholesterol depletion impaired lipid raft integrity thereby affecting 5-HT3 receptor function, whereas the antagonistic effects of antidepressants were not altered. In conclusion, most antidepressants directly antagonize 5-HT3 receptor activity. 5-HT3 receptor function per se appears to depend on lipid raft integrity, which is, however, not a prerequisite for the modulatory potency of antidepressants at this receptor.