Biophysics of BK Channel Gating

Pantazis, Antonios; Olcese, Riccardo

doi:10.1016/bs.irn.2016.03.013

Cited by 20 publications

(20 citation statements)

References 289 publications

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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%

“…Large conductance Ca 2+ -and voltage-activated K + channels (BK, Slo1, Maxi-K, KCa1.1, KCNMA1 gene) are widely distributed and opened by the synergistic action of depolarization and intracellular Ca 2+ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), with intracellular Mg 2+ modulating the activation (18,19). Open BK channels allow the outward movement of intracellular K + , which drives the membrane potential in a negative direction, decreasing the excitability of cells by deactivating voltage dependent Na + and Ca 2+ channels.…”

Section: Introductionmentioning

confidence: 99%

“…It is known that the BK channel is of modular design, with the voltage sensors and pore gate forming the transmembrane domain of the channel (TMD), and the large cytosolic domain (CTD) containing the Ca 2+ sensors (3,4,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Removing the CTD removes all Ca 2+ sensitivity (29), leaving a voltage gated channel (29,30).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Slo1 | BK | KCa1.1 | electrophysiology | molecular dynamics L arge-conductance Ca 2+ -and voltage-gated (Slo1) big potassium (BK) channels function generally as negative-feedback components in cellular electrical excitability by mediating K + flux in response to depolarization of transmembrane voltage (V m ) and/or an increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ). Changes in V m and binding of Ca 2+ are coupled to opening and closing of the ion conduction gate (1)(2)(3). The exact nature of the Slo1 ion conduction gate is yet to be revealed.…”

mentioning

confidence: 99%

Large-conductance Ca ²⁺ - and voltage-gated K ⁺ channels form and break interactions with membrane lipids during each gating cycle

Tian

Heinemann

Hoshi

2019

Proc. Natl. Acad. Sci. U.S.A.

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Membrane depolarization and intracellular Ca 2+ promote activation of the large-conductance Ca 2+ -and voltage-gated (Slo1) big potassium (BK) channel. We examined the physical interactions that stabilize the closed and open conformations of the ion conduction gate of the human Slo1 channel using electrophysiological and computational approaches. The results show that the closed conformation is stabilized by intersubunit ion-ion interactions involving negative residues (E321 and E324) and positive residues ( 329 RKK 331 ) at the cytoplasmic ends of the transmembrane S6 segments ("RKK ring"). When the channel gate is open, the RKK ring is broken and the positive residues instead make electrostatic interactions with nearby membrane lipid oxygen atoms. E321 and E324 are stabilized by water. When the 329 RKK 331 residues are mutated to hydrophobic amino acids, these residues form even stronger hydrophobic interactions with the lipid tails to promote the open conformation, shifting the voltage dependence of activation to the negative direction by up to 400 mV and stabilizing the selectivity filter region. Thus, the RKK segment forms electrostatic interactions with oxygen atoms from two sources, other amino acid residues (E321/E324), and membrane lipids, depending on the gate status. Each time the channel opens and closes, the aforementioned interactions are formed and broken. This lipid-dependent Slo1 gating may explain how amphipathic signaling molecules and pharmacologically active agents influence the channel activity, and a similar mechanism may be operative in other ion channels.Slo1 | BK | KCa1.1 | electrophysiology | molecular dynamics L arge-conductance Ca 2+ -and voltage-gated (Slo1) big potassium (BK) channels function generally as negative-feedback components in cellular electrical excitability by mediating K + flux in response to depolarization of transmembrane voltage (V m ) and/or an increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ). Changes in V m and binding of Ca 2+ are coupled to opening and closing of the ion conduction gate (1-3). The exact nature of the Slo1 ion conduction gate is yet to be revealed. Subtle changes in the selectivity filter (4-6) and dewetting of the channel cavity (7) have been suggested as the possible underlying mechanisms. Unlike in canonical voltage-gated K + channels (8), four Slo1 S6 segments, each capable of rotational movements (9), remain wide apart enough even when the main gate elsewhere is closed, allowing some inhibitors to enter the channel cavity from the intracellular side (4, 10).Gating of the Slo1 channel is subject to numerous regulatory influences. The channel gene undergoes extensive splicing, producing variants differing at many loci including the area immediately C terminal to S6 (11). Pore-forming Slo1 subunits coassemble with βand γ-subunits, altering multiple properties such as gating and pharmacology (12). Further, many small molecules, including H 2 S, hemin, and various fatty acids and lipids, alter Slo1 gating (13). For example, exogenous i...

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“…BK channels link chemical and electrical signaling through Ca 2+ -dependent voltage-operated activation (Pantazis and Olcese, 2016 ). Moreover, a wide range of intracellular ligands enable BK channels to be gated or modified (Piskorowski and Aldrich, 2006 ).…”

Section: Structural Characteristics and Physiological Functions Of Bkmentioning

confidence: 99%

Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

2017

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Large-conductance calcium-activated potassium channels (BK channels) belong to a family of Ca2+-sensitive voltage-dependent potassium channels and play a vital role in various physiological activities in the human body. The renin-angiotensin-aldosterone system is acknowledged as being vital in the body's hormone system and plays a fundamental role in the maintenance of water and electrolyte balance and blood pressure regulation. There is growing evidence that the renin-angiotensin-aldosterone system has profound influences on the expression and bioactivity of BK channels. In this review, we focus on the molecular mechanisms underlying the regulation of BK channels mediated by the renin-angiotensin-aldosterone system and its potential as a target for clinical drugs.

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Biophysics of BK Channel Gating

Cited by 20 publications

References 289 publications

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

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

Large-conductance Ca ²⁺ - and voltage-gated K ⁺ channels form and break interactions with membrane lipids during each gating cycle

Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

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Biophysics of BK Channel Gating

Cited by 20 publications

References 289 publications

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

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

Large-conductance Ca 2+ - and voltage-gated K + channels form and break interactions with membrane lipids during each gating cycle

Molecular Mechanisms Underlying Renin-Angiotensin-Aldosterone System Mediated Regulation of BK Channels

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

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

Large-conductance Ca ²⁺ - and voltage-gated K ⁺ channels form and break interactions with membrane lipids during each gating cycle