title: TREK-1 isoforms generated by alternative translation initiation display different susceptibility to the antidepressant fluoxetine.
abstract: Two-pore-domain K(+) (K(2)P) channels are highly expressed in neurons and cardiac myocytes. In this study we investigated the potency of the antidepressant fluoxetine to inhibit brain and cardiac K(2)P channels, TREK-1, TASK-1 and THIK-1. Maximal sensitivity was detected for TREK-1, which was inhibited by 77% when expressed in HEK-293 cells and Xenopus oocytes. Alternative translation initiation (ATI) generates two different protein products from a single transcript of TREK-1. Electrophysiological analysis of two polypeptides engineered by mutagenesis (TREK-1[M53I], TREK-1[ΔN52]) revealed reduced current amplitude and K(+) selectivity of the truncated TREK-1 isoform. The sensitivity of TREK-1[ΔN52] to fluoxetine decreased by 70%, indicating that the first 52 amino acids are essential for TREK-1 sensitivity to this drug.
authors: Institute of Physiology, University of Würzburg, Würzburg, Germany.
authors: Michaela
authors: M
authors: Eckert
authors: Brigitte
authors: B
authors: Egenberger
authors: Frank
authors: F
authors: Döring
authors: Erhard
authors: E
authors: Wischmeyer
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D005473:Fluoxetine / Q000378:metabolism / Q000494:pharmacology*; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis; D032383:Myocytes, Cardiac / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009865:Oocytes; D018408:Patch-Clamp Techniques; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D018687:Antidepressive Agents, Second-Generation; D004247:DNA; D005473:Fluoxetine; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; D020033:Protein Isoforms; D017367:Selective Serotonin Reuptake Inhibitors; C486603:KCNK13 protein, human; C103742:potassium channel protein TREK-1; C420132:potassium channel subfamily K member 3