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

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[Delta N52]) revealed reduced current amplitude and K(+) selectivity of the truncated TREK-1 isoform. The sensitivity of TREK-1[Delta N52] to fluoxetine decreased by 70%, indicating that the first 52 amino acids are essential for TREK-1 sensitivity to this drug. (C) 2011 Elsevier Ltd. All rights reserved.