Tuning the gate and the gear: The LRRC26 (γ1) subunit modulates intrinsic gating and voltage-sensor coupling of the BK channel

Abstract

Association of auxiliary subunits ({beta}1-4 and {gamma}1-4) with the pore-forming subunit of the calcium- and voltage-activated potassium (BK) channel provides functional diversity. {gamma}1 promotes a significant leftward shift of the voltage activation curve, ensuring the adequate functioning of secretory glands, allowing the BK channel to release K+ at the cells resting Ca2+ concentration. Given its physiological importance, it is crucial to elucidate the mechanisms of {gamma}1 action. However, structural and functional studies have yielded conflicting conclusions regarding the modulation of BK channels by {gamma}1. Here, using macroscopic, single-channel, and gating current measurements, we demonstrate that at zero mV {gamma}1 increases 92-fold the equilibrium constant that defines the closed- open transition by destabilizing the channels closed configuration and enhancing the coupling between the voltage sensor and the pore domain, without affecting voltage-sensor activation. These results suggest that {gamma}1 not only causes an increase in the energetic coupling between the voltage sensors and the pore but mainly enhances the channel opening reaction. TeaserThe {gamma}1 subunit favors the BK channel pore opening by destabilizing its closed configuration.