Defining the BK channel domains required for β1-subunit modulation

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 alpha-subunits, associate with auxiliary beta-subunits in a tissue-specific manner, modifying the channel's gating properties. The BK beta 1-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 17 beta-estradiol. The beta 1-subunit is essential for normal regulation of vascular smooth muscle contractility and blood pressure. Little is known, however, about the molecular mechanisms of beta 1-subunit modulation of alpha-subunits. Here we show that the beta 1-subunit's modulation of the Ca2+ and 17 beta-estradiol sensitivities can be dissociated from its effects on gating kinetics by truncation of the a-subunit's extracellular N-terminal residues. The BK alpha-subunit N terminus interacts uniquely with the beta 1-subunit: beta 2 regulation of the a-subunit is unaltered by truncation of the N terminus. Although the functional interaction of alpha and beta 1 requires the N-terminal tail of alpha, the physical association requires the S1, S2, and S3 transmembrane helices of a.