TREK-1 isoforms generated by alternative translation initiation display different susceptibility to the antidepressant fluoxetine

Michaela Eckert; Brigitte Egenberger; Frank Döring; Erhard Wischmeyer

doi:10.1016/j.neuropharm.2011.06.020

TREK-1 isoforms generated by alternative translation initiation display different susceptibility to the antidepressant fluoxetine

Neuropharmacology. 2011 Oct-Nov;61(5-6):918-23. doi: 10.1016/j.neuropharm.2011.06.020. Epub 2011 Jul 1.

Authors

Michaela Eckert¹, Brigitte Egenberger, Frank Döring, Erhard Wischmeyer

Affiliation

¹ Institute of Physiology, University of Würzburg, Würzburg, Germany.

PMID: 21740918
DOI: 10.1016/j.neuropharm.2011.06.020

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antidepressive Agents, Second-Generation / metabolism
Antidepressive Agents, Second-Generation / pharmacology*
DNA / metabolism
Fluoxetine / metabolism
Fluoxetine / pharmacology*
Genetic Vectors
HEK293 Cells
Humans
Membrane Proteins / analysis
Myocytes, Cardiac / metabolism
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neurons / metabolism
Oocytes
Patch-Clamp Techniques
Potassium Channels, Tandem Pore Domain / antagonists & inhibitors*
Potassium Channels, Tandem Pore Domain / genetics
Potassium Channels, Tandem Pore Domain / metabolism
Protein Biosynthesis
Protein Isoforms / genetics
Protein Isoforms / metabolism
Selective Serotonin Reuptake Inhibitors / metabolism
Selective Serotonin Reuptake Inhibitors / pharmacology
Sensitivity and Specificity
Transfection
Xenopus laevis

Substances

Antidepressive Agents, Second-Generation
KCNK13 protein, human
Membrane Proteins
Nerve Tissue Proteins
Potassium Channels, Tandem Pore Domain
Protein Isoforms
Serotonin Uptake Inhibitors
potassium channel protein TREK-1
Fluoxetine
potassium channel subfamily K member 3
DNA