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Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229

Correspondence to Robert Brenner: brennerr{at}uthscsa.edu

Large-conductance (BK-type) Ca²⁺-activated potassium channels are activated by membrane depolarization and cytoplasmic Ca²⁺. BK channels are expressed in a broad variety of cells and have a corresponding diversity in properties. Underlying much of the functional diversity is a family of four tissue-specific accessory subunits (ß1–ß4). Biophysical characterization has shown that the ß4 subunit confers properties of the so-called "type II" BK channel isotypes seen in brain. These properties include slow gating kinetics and resistance to iberiotoxin and charybdotoxin blockade. In addition, the ß4 subunit reduces the apparent voltage sensitivity of channel activation and has complex effects on apparent Ca²⁺ sensitivity. Specifically, channel activity at low Ca²⁺ is inhibited, while at high Ca²⁺, activity is enhanced. The goal of this study is to understand the mechanism underlying ß4 subunit action in the context of a dual allosteric model for BK channel gating. We observed that ß4's most profound effect is a decrease in P_o (at least 11-fold) in the absence of calcium binding and voltage sensor activation. However, ß4 promotes channel opening by increasing voltage dependence of P_o-V relations at negative membrane potentials. In the context of the dual allosteric model for BK channels, we find these properties are explained by distinct and opposing actions of ß4 on BK channels. ß4 reduces channel opening by decreasing the intrinsic gating equilibrium (L₀), and decreasing the allosteric coupling between calcium binding and voltage sensor activation (E). However, ß4 has a compensatory effect on channel opening following depolarization by shifting open channel voltage sensor activation (Vh_o) to more negative membrane potentials. The consequence is that ß4 causes a net positive shift of the G-V relationship (relative to subunit alone) at low calcium. At higher calcium, the contribution by Vh_o and an increase in allosteric coupling to Ca²⁺ binding (C) promotes a negative G-V shift of +ß4 channels as compared to subunits alone. This manner of modulation predicts that type II BK channels are downregulated by ß4 at resting voltages through effects on L₀. However, ß4 confers a compensatory effect on voltage sensor activation that increases channel opening during depolarization.

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