An Extracellular Domain of BK Channel β1 Accessory Subunit Modulates the Activities of Voltage Sensor and Gate

Abstract

A family of tissue-specific auxiliary β subunits modulate large conductance, voltage- and calcium- activated potassium (BK) channel gating properties to suit their diverse function. Paradoxically, β subunits both promote BK channel activation through a stabilization of voltage-sensor activation, and reduce BK channel openings through an increased energetic barrier of the closed-to-open transition. The molecular determinants underlying β-subunit function, including the dual gating effects remain unknown. Here, we report the first identification of a β1 functional domain consisting of Y74, S104, Y105 and I106 residues located in the extracellular loop of β1. These amino acids reside within two regions of highest conservation among related β1, β2 and β4 subunits. Analysis in the context of the Horrigan-Aldrich gating model revealed that this domain functions to both promote voltage-sensor activation, but also reduce intrinsic gating. Free energy calculations suggest that the dual effects of the β1 Y74, S104-I106 domain can be largely accounted for by a relative destabilization of channels in open states that have few voltage sensors activated. These results suggest a unique and novel mechanism for β subunit modulation of voltage-gated potassium channels wherein interactions between extracellular β subunit residues with the external portions of the gate and voltage sensor regulate channel opening.