title: Modulation of ligand-gated ion channels as a novel pharmacological principle.
abstract: The present study investigated the functional antagonism of different antidepressants on 5-HT (3) 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-HT (3A) cells and hippocampal neurons. The characterization of the antagonism of antidepressants was made by the displacement of [ (3)H]GR65630 binding. For membrane fractionation, sucrose density gradient centrifugation was used. Gradient fractions were assayed for antidepressant concentrations by HPLC; 5-HT (3) 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-HT (3) receptor. Moreover, some of these compounds were enriched within lipid rafts. Cholesterol depletion impaired lipid raft integrity thereby affecting 5-HT (3) receptor function, whereas the antagonistic effects of antidepressants were not altered.In conclusion, most antidepressants directly antagonize 5-HT (3) receptor activity. 5-HT (3) 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.
authors.affiliation: Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Germany. Caroline.Nothdurfter@med.uni-muenchen.de
authors.forename: C
authors.initials: C
authors.lastname: Nothdurfter
authors.forename: S
authors.initials: S
authors.lastname: Tanasic
authors.forename: G
authors.initials: G
authors.lastname: Rammes
authors.forename: R
authors.initials: R
authors.lastname: Rupprecht
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D058446:Ligand-Gated Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D021962:Membrane Microdomains / Q000187:drug effects; D051379:Mice; D009447:Neuroblastoma; D018408:Patch-Clamp Techniques; D051381:Rats; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D014326:Tropanes / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D007093:Imidazoles; D007211:Indoles; D058446:Ligand-Gated Ion Channels; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D014326:Tropanes; C059068:GR 65630; C042253:bemesetron