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Large-conductance, voltage-, and Ca²⁺-dependent K⁺ (BK) channels are broadly expressed in various tissues to modulate neuronal activity, smooth muscle contraction, and secretion. BK channel activation depends on the interactions among the voltage sensing domain (VSD), the cytosolic domain (CTD), and the pore gate domain (PGD) of the Slo1 α-subunit, and is further regulated by accessory β subunits (β1-β4). How β subunits fine-tune BK channel activation is critical to understand the tissue-specific functions of BK channels. Multiple sites in both Slo1 and the β subunits have been identified to contribute to the interaction between Slo1 and the β subunits. However, it is unclear whether and how the interdomain interactions among the VSD, CTD, and PGD are altered by the β subunits to affect channel activation. Here we show that human β1 and β2 subunits alter interactions between bound Mg²⁺ and gating charge R213 and disrupt the disulfide bond formation at the VSD-CTD interface of mouse Slo1, indicating that the β subunits alter the VSD-CTD interface. Reciprocally, mutations in the Slo1 that alter the VSD-CTD interaction can specifically change the effects of the β1 subunit on the Ca²⁺ activation and of the β2 subunit on the voltage activation. Together, our data suggest a novel mechanism by which the β subunits modulated BK channel activation such that a β subunit may interact with the VSD or the CTD and alter the VSD-CTD interface of the Slo1, which enables the β subunit to have effects broadly on both voltage and Ca²⁺-dependent activation.

The Interface between Membrane-Spanning and Cytosolic Domains in Ca2+-Dependent K+ Channels Is Involved in Subunit Modulation of Gating