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Correspondence to Robert Brenner: brennerr{at}uthscsa.edu
Large conductance, Ca2+- and voltage-activated K+ (BK) channels are exquisitely regulated to suit their diverse roles in a large variety of physiological processes. BK channels are composed of pore-forming 
subunits and a family of tissue-specific accessory ß subunits. The smooth muscle–specific ß1 subunit has an essential role in regulating smooth muscle contraction and modulates BK channel steady-state open probability and gating kinetics. Effects of ß1 on channel's gating energetics are not completely understood. One of the difficulties is that it has not yet been possible to measure the effects of ß1 on channel's intrinsic closed-to-open transition (in the absence of voltage sensor activation and Ca2+ binding) due to the very low open probability in the presence of ß1. In this study, we used a mutation of the subunit (F315Y) that increases channel openings by greater than four orders of magnitude to directly compare channels' intrinsic open probabilities in the presence and absence of the ß1 subunit. Effects of ß1 on steady-state open probabilities of both wild-type and the F315Y mutation were analyzed using the dual allosteric HA model. We found that mouse ß1 has two major effects on channel's gating energetics. ß1 reduces the intrinsic closed-to-open equilibrium that underlies the inhibition of BK channel opening seen in submicromolar Ca2+. Further, PO measurements at limiting slope allow us to infer that ß1 shifts open channel voltage sensor activation to negative membrane potentials, which contributes to enhanced channel opening seen at micromolar Ca2+ concentrations. Using the F315Y subunit with deletion mutants of ß1, we also demonstrate that the small N- and C-terminal intracellular domains of ß1 play important roles in altering channel's intrinsic opening and voltage sensor activation. In summary, these results demonstrate that ß1 has distinct effects on BK channel intrinsic gating and voltage sensor activation that can be functionally uncoupled by mutations in the intracellular domains.
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