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

Association of auxiliary subunits (β1-4 and γ1-4) with the pore-forming α subunit of the calcium- and voltage-activated potassium (BK) channel provides functional diversity. γ1 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 cell's resting Ca2+ concentration. Given its physiological importance, it is crucial to elucidate the mechanisms of γ1 action. However, structural and functional studies have yielded conflicting conclusions regarding the modulation of BK channels by γ1. Here, using macroscopic, single-channel, and gating current measurements, we demonstrate that at zero mV γ1 increases 92-fold the equilibrium constant that defines the closed-open transition by destabilizing the channel's closed configuration and enhancing the coupling between the voltage sensor and the pore domain, without affecting voltage-sensor activation. These results suggest that γ1 not only causes an increase in the energetic coupling between the voltage sensors and the pore but mainly enhances the channel opening reaction.