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

Two-pore-domain K+ (K2P) 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 K2P 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.

► K2P potassium channels display different sensitivity to clinically used antidepressants.
► The K2P channel TREK-1 is the major molecular target of fluoxetine.
► The natively expressed short isoform of TREK-1 is less sensitive to fluoxetine compared with the long isoform.
► The N-terminus of the channel protein interacts with antidepressants.