Voltage-dependent dynamics of the BK channel cytosolic gating ring are coupled to the membrane-embedded voltage sensor

Miranda, Pablo; Holmgren, Miguel; Giráldez, Teresa

doi:10.7554/elife.40664

Cited by 19 publications

(27 citation statements)

References 71 publications

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“…The voltage dependence of Ca 2+ -dependent gating ring rearrangements (Miranda et al, 2013; Miranda et al, 2018) and RCK1 site occupancy (Sweet and Cox, 2008; Savalli et al, 2012; Miranda et al, 2018) as well as the perturbation of VSD movements by Ca 2+ binding (Savalli et al, 2012) support the idea that the energetic interaction between both specialized sensors may be crucial for BK channel activation. The physical CTD-VSD interface has been suggested to provide the structure capable of mediating the crosstalk between these sensory modules and their synergy in activating the pore domain (Yang et al, 2007; Sun et al, 2013; Tao et al, 2017; Zhang et al, 2017).…”

Section: Introductionmentioning

confidence: 71%

Calcium-driven regulation of voltage-sensing domains in BK channels

Lorenzo-Ceballos

Carrasquel-Ursulaez

Castillo

et al. 2019

eLife

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Allosteric interactions between the voltage-sensing domain (VSD), the Ca2+-binding sites, and the pore domain govern the mammalian Ca2+- and voltage-activated K+ (BK) channel opening. However, the functional relevance of the crosstalk between the Ca2+- and voltage-sensing mechanisms on BK channel gating is still debated. We examined the energetic interaction between Ca2+ binding and VSD activation by investigating the effects of internal Ca2+ on BK channel gating currents. Our results indicate that Ca2+ sensor occupancy has a strong impact on VSD activation through a coordinated interaction mechanism in which Ca2+ binding to a single α-subunit affects all VSDs equally. Moreover, the two distinct high-affinity Ca2+-binding sites contained in the C-terminus domains, RCK1 and RCK2, contribute equally to decrease the free energy necessary to activate the VSD. We conclude that voltage-dependent gating and pore opening in BK channels is modulated to a great extent by the interaction between Ca2+ sensors and VSDs.

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Section: Introductionmentioning

confidence: 71%

Calcium-driven regulation of voltage-sensing domains in BK channels

Lorenzo-Ceballos

Carrasquel-Ursulaez

Castillo

et al. 2019

eLife

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“…The αB Helix/VSD Interface is Required for Effective Voltage and Ca 2+ Activation of BK Channels. Functional studies have suggested that voltage and Ca 2+ sensors of BK channels interact, as summarized in the Introduction (6,13,15,28,30,40,41,43,44), and that the AC (N-lobe) region of the CTD is involved (25,51). Structural studies have identified a potential structural pathway to couple Ca 2+ sensors in the CTD with voltage sensors in the TMD (16,17,31).…”

Section: Discussionmentioning

confidence: 99%

“…However, there are also indications of some potential differences in activation pathways, as Ca 2+ binding is voltage dependent at the RCK1 Ca 2+ site, but not at the Ca 2+ bowl site (41), and strong correlation has been observed between VSD function and RCK1 conformational changes, but not between RCK2 and VSD function (44). Additional evidence for some possible differences in the RCK1 Ca 2+ site activation pathway and the Ca 2+ bowl activation pathway are our observations that disruption of the αB helix with L390P reduced the fractional contribution to Ca 2+ sensitivity from RCK1 Ca 2+ sites more than from Ca 2+ bowl sites ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Ca 2+ sensor occupancy left shifts the Q-V curves, with strong allosteric coupling between Ca 2+ -binding sites and voltage sensors (43). Strong correlations have been observed between VSD rearrangements and conformational changes in the CTD, which support a pathway that couples Ca 2+ binding to channel opening through the voltage sensor (44). Mg 2+ binding between the VSD and the CTD directly couples voltage, Ca 2+ , and Mg 2+ sensors (19,28).…”

Section: Introductionmentioning

confidence: 88%

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Coupling of Ca²⁺and voltage activation in BK channels through the αB helix/voltage sensor interface

Geng

Deng²,

Zhang³

et al. 2020

Preprint

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Office phone: 305 243-6236. AbstractLarge conductance Ca 2+ and voltage activated K + (BK) channels control membrane excitability in many cell types. BK channels are tetrameric. Each subunit is comprised of a voltage sensor domain (VSD), a central pore gate domain, and a large cytoplasmic domain (CTD) that contains the Ca 2+ sensors. While it is known that BK channels are activated by voltage and Ca 2+ , and that voltage and Ca 2+ activations interact, less is known about the mechanisms involved. We now explore mechanism by examining the gating contribution of an interface formed between the VSDs and the αB helices located at the top of the CTDs. Proline mutations in the αB helix greatly decreased voltage activation while having negligible effects on gating currents. Analysis with the HCA model indicated a decreased coupling between voltage sensors and pore gate. Proline mutations decreased Ca 2+ activation for both Ca 2+ bowl and RCK1 Ca 2+ sites, suggesting that both high affinity Ca 2+ sites transduce their effect, at least in part, through the αB helix. Mg 2+ activation was also decreased. The crystal structure of the CTD with proline mutation L390P showed a flattening of the first helical turn in the αB helix compared to WT, without other notable differences in the CTD, indicating structural change from the mutation was confined to the αB helix. These findings indicate that an intact αB helix/VSD interface is required for effective coupling of Ca 2+ binding and voltage depolarization to pore opening, and that shared Ca 2+ and voltage transduction pathways involving the αB helix may be involved. Slo1 channel | BK channel | Ca 2+ -activated K + channel | allosteric coupling | patch clamp SignificanceLarge conductance BK (Slo1) K + channels are activated by voltage, Ca 2+ , and Mg 2+ to modulate membrane excitability in neurons, muscle, and other cells. BK channels are of modular design, with pore-gate and voltage sensors as transmembrane domains and a large cytoplasmic domain CTD containing the Ca 2+ sensors. Previous observations suggest that voltage and Ca 2+ sensors interact, but less is known about this interaction and its involvement in the gating process. We show that a previously identified structural interface between the CTD and voltage sensors is required for effective activation by both voltage and Ca 2+ , suggesting that these processes may share common allosteric activation pathways. Such knowledge should help explain disease processes associated with BK channel dysfunction.

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“…In structure, the BK channels mainly consist of two subunits: pore-forming α subunit and auxiliary β subunit, which form a tetramer (Ge et al, 2014). The α subunit is composed of seven transmembrane domains (S0-S6) (Miranda et al, 2018), including extracellular N terminals, voltage-sensitive domains, and cytoplasmic C ends with calcium and other regulatory molecule binding sites. There are four subtypes of β subunits (β1-β4) (Bhattarai et al, 2014), and mainly β1 subunit is in vascular smooth muscle cells.…”

Section: Bk Channel Dysfunction In Diabetic Coronary Arterymentioning

confidence: 99%

BK Channel Dysfunction in Diabetic Coronary Artery: Role of the E3 Ubiquitin Ligases

Qian

Liu

et al. 2020

Front. Physiol.

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Diabetic coronary arterial disease is a leading cause of morbidity and mortality in diabetic patients. The impaired function of large-conductance calcium-activated potassium channels (BK channels) is involved in diabetic coronary arterial disease. Many studies have indicated that the reduced BK channel expression in diabetic coronary artery is attributed to ubiquitin-mediated protein degradation by the ubiquitin-proteasome system. This review focuses on the influence and the mechanisms of BK channel regulation by E3 ubiquitin ligases in diabetic coronary arterial disease. Thus, BK channels regulated by E3 ubiquitin ligase may play a pivotal role in the coronary pathogenesis of diabetic mellitus and, as such, is a potentially attractive target for therapeutic intervention.

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Voltage-dependent dynamics of the BK channel cytosolic gating ring are coupled to the membrane-embedded voltage sensor

Cited by 19 publications

References 71 publications

Calcium-driven regulation of voltage-sensing domains in BK channels

Calcium-driven regulation of voltage-sensing domains in BK channels

Coupling of Ca²⁺and voltage activation in BK channels through the αB helix/voltage sensor interface

BK Channel Dysfunction in Diabetic Coronary Artery: Role of the E3 Ubiquitin Ligases

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Voltage-dependent dynamics of the BK channel cytosolic gating ring are coupled to the membrane-embedded voltage sensor

Cited by 19 publications

References 71 publications

Calcium-driven regulation of voltage-sensing domains in BK channels

Calcium-driven regulation of voltage-sensing domains in BK channels

Coupling of Ca2+and voltage activation in BK channels through the αB helix/voltage sensor interface

BK Channel Dysfunction in Diabetic Coronary Artery: Role of the E3 Ubiquitin Ligases

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Coupling of Ca²⁺and voltage activation in BK channels through the αB helix/voltage sensor interface