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Regulation of large-conductance Ca2+- and voltage-gated K+ channels by electrostatic interactions with auxiliary β subunits

Large-conductance Ca2+- and voltage-gated K+ (BK KCa1.1) channel complexes include pore-forming Slo1 α subunits and often auxiliary β subunits, latter of which noticeably modify the channel’s pharmacological and gating characteristics. In the absence of intracellular Ca2+, β1 and β4 modestly shift the overall voltage dependence of the channel to the positive direction by decreasing the probability that the ion conduction gate is open without any allosteric influence from the channel’s voltage or Ca2+ sensors. This intrinsic open probability is also critically regulated by the intracellular-facing 329RKK331 segment of human Slo1 (hSlo1) downstream of the transmembrane segment S6 in association with two negatively charged residues in S6 (E321 and E324) (Tian et al., Proc Natl Acad Sci USA, 116, 8591-8596, 2019). This study examined how β1/β4 and the RKK segment function together to control the channel gate. With select mutations in the RKK segment, inclusions of β1 or β4 can dramatically increase the intrinsic gate opening probability and shift the overall voltage dependence of the channel to the negative direction by up to 200 mV without Ca2+. This remarkable shift is mediated at least in part by electrostatic interactions between the Slo1 RKK and β N-terminal segments as suggested by the results of double-mutant cycle analysis, ionic strength experiments, and molecular modelling. With or without auxiliary β subunits, the Slo1 RKK and E321/E324 segments are thus critical determinants of the intrinsic open probability of the ion conduction gate and changes in the electrostatic environment near the RKK-EE segments are a potential mechanism of pharmacological gating modifiers.