Dataset Information

The interface between membrane-spanning and cytosolic domains in Ca²+-dependent K+ channels is involved in ? subunit modulation of gating.

ABSTRACT: 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 ?-subunit, and is further regulated by accessory ? subunits (?1-?4). How ? subunits fine-tune BK channel activation is critical to understand the tissue-specific functions of BK channels. Multiple sites in both Slo1 and the ? subunits have been identified to contribute to the interaction between Slo1 and the ? subunits. However, it is unclear whether and how the interdomain interactions among the VSD, CTD, and PGD are altered by the ? subunits to affect channel activation. Here we show that human ?1 and ?2 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 ? subunits alter the VSD-CTD interface. Reciprocally, mutations in the Slo1 that alter the VSD-CTD interaction can specifically change the effects of the ?1 subunit on the Ca²? activation and of the ?2 subunit on the voltage activation. Together, our data suggest a novel mechanism by which the ? subunits modulated BK channel activation such that a ? subunit may interact with the VSD or the CTD and alter the VSD-CTD interface of the Slo1, which enables the ? subunit to have effects broadly on both voltage and Ca²?-dependent activation.

SUBMITTER: Sun X

PROVIDER: S-EPMC3718382 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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The interface between membrane-spanning and cytosolic domains in Ca²+-dependent K+ channels is involved in β subunit modulation of gating.

Sun Xiaohui X Shi Jingyi J Delaloye Kelli K Yang Xiao X Yang Huanghe H Zhang Guohui G Cui Jianmin J

The Journal of neuroscience : the official journal of the Society for Neuroscience 20130701 27

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-specifi ...[more]

PMID: 23825428

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Project description:Large-conductance (BK-type) Ca(2+)-activated potassium channels are activated by membrane depolarization and cytoplasmic Ca(2+). 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 (beta1-beta4). Biophysical characterization has shown that the beta4 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 beta4 subunit reduces the apparent voltage sensitivity of channel activation and has complex effects on apparent Ca(2+) sensitivity. Specifically, channel activity at low Ca(2+) is inhibited, while at high Ca(2+), activity is enhanced. The goal of this study is to understand the mechanism underlying beta4 subunit action in the context of a dual allosteric model for BK channel gating. We observed that beta4'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, beta4 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 beta4 on BK channels. beta4 reduces channel opening by decreasing the intrinsic gating equilibrium (L(0)), and decreasing the allosteric coupling between calcium binding and voltage sensor activation (E). However, beta4 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 beta4 causes a net positive shift of the G-V relationship (relative to alpha subunit alone) at low calcium. At higher calcium, the contribution by Vh(o) and an increase in allosteric coupling to Ca(2+) binding (C) promotes a negative G-V shift of alpha+beta4 channels as compared to alpha subunits alone. This manner of modulation predicts that type II BK channels are downregulated by beta4 at resting voltages through effects on L(0). However, beta4 confers a compensatory effect on voltage sensor activation that increases channel opening during depolarization.

Dataset Information

The interface between membrane-spanning and cytosolic domains in Ca²+-dependent K+ channels is involved in ? subunit modulation of gating.

Publications

The interface between membrane-spanning and cytosolic domains in Ca²+-dependent K+ channels is involved in β subunit modulation of gating.

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