Defining the BK channel domains required for β1-subunit modulation

Abstract

In a wide variety of cell types, including neurons and smooth muscle cells, activation of the large-conductance voltage- and Ca²⁺-activated K⁺ (BK) channels causes transient membrane hyperpolarization, thereby regulating cellular excitability. Similar to other voltage-gated ion channels, BK channels, a tetramer of α-subunits, associate with auxiliary β-subunits in a tissue-specific manner, modifying the channel's gating properties. The BK β1-subunit, which is expressed in smooth muscle, increases the apparent Ca²⁺ sensitivity (marked by a hyperpolarizing shift in the conductance–voltage relationship at a given Ca²⁺ concentration), slows macroscopic activation and deactivation, and is required for channel activation by 17β-estradiol. The β1-subunit is essential for normal regulation of vascular smooth muscle contractility and blood pressure. Little is known, however, about the molecular mechanisms of β1-subunit modulation of α-subunits. Here we show that the β1-subunit's modulation of the Ca²⁺ and 17β-estradiol sensitivities can be dissociated from its effects on gating kinetics by truncation of the α-subunit's extracellular N-terminal residues. The BK α-subunit N terminus interacts uniquely with the β1-subunit: β2 regulation of the α-subunit is unaltered by truncation of the N terminus. Although the functional interaction of α and β1 requires the N-terminal tail of α, the physical association requires the S1, S2, and S3 transmembrane helices of α.

• β-subunit
• calcium sensitivity
• potassium channel