A Direct Interaction between Cyclodextrins and TASK Channels Decreases the Leak Current in Cerebellar Granule Neurons

Biology (Basel). 2022 Jul 23;11(8):1097. doi: 10.3390/biology11081097.

Abstract

Two pore domain potassium channels (K2P) are strongly expressed in the nervous system (CNS), where they play a central role in excitability. These channels give rise to background K+ currents, also known as IKSO (standing-outward potassium current). We detected the expression in primary cultured cerebellar granule neurons (CGNs) of TWIK-1 (K2P1), TASK-1 (K2P3), TASK-3 (K2P9), and TRESK (K2P18) channels by immunocytochemistry and their association with lipid rafts using the specific lipids raft markers flotillin-2 and caveolin-1. At the functional level, methyl-β-cyclodextrin (MβCD, 5 mM) reduced IKSO currents by ~40% in CGN cells. To dissect out this effect, we heterologously expressed the human TWIK-1, TASK-1, TASK-3, and TRESK channels in HEK-293 cells. MβCD directly blocked TASK-1 and TASK-3 channels and the covalently concatenated heterodimer TASK-1/TASK-3 currents. Conversely, MβCD did not affect TWIK-1- and TRESK-mediated K+ currents. On the other hand, the cholesterol-depleting agent filipin III did not affect TASK-1/TASK-3 channels. Together, the results suggest that neuronal background K+ channels are associated to lipid raft environments whilst the functional activity is independent of the cholesterol membrane organization.

Keywords: K+ leak currents; K2P channels; cerebellar granule neurons; cyclodextrin.

Grant support

This work was supported by Fondecyt 1191133 (F.V., W.G. and L.Z.), Fondecyt 1211838 to M.A.C., and FIC-R “Portafolio de servicios para la caracterización de blancos terapéuticos para el tratamiento de cáncer y enfermedades crónicas no transmisibles” (W.G. and L.Z.).