The Contribution of RCK Domains to Human BK Channel Allosteric Activation

Savalli, Nicoletta; Pantazis, Antonios; Yusifov, Taleh N.; Sigg, Daniel; Olcese, Riccardo

doi:10.1074/jbc.m112.346171

Cited by 39 publications

(54 citation statements)

References 67 publications

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“…To optically track the conformational transitions of each VSD in human Ca V 1.2 channels, we used voltage-clamp fluorometry (VCF), a hybrid electrophysiological-optical approach (28)(29)(30)(31)(32)(33)(34). A Cys was introduced at the extracellular flank of S4 helices in each VSD of the Ca V 1.2 pore-forming subunit (α 1C ) and labeled with a fluorophore (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The voltagedependent rearrangements of each VSD were optically tracked by a cutopen oocyte Vaseline gap voltage clamp complemented with fluorometry (35,36,55) as previously described (30,(32)(33)(34). Complete details are in SI Appendix.…”

Section: Methodsmentioning

confidence: 99%

“…An alternative to the obligatory models considered is the notion, inspired by previous work on Ca V (27,44,45), large-conductance voltageand Ca 2+ -gated (BK) channels (34,46), and K V 7.1 channels (47), that pore opening is facilitated by VSD activation through an allosteric gating mechanism: that is, each VSD contributes a weak (i.e., quantifiable) characteristic energy to the stabilization of the open state. An allosteric model of Ca V 1.2 activation is represented by scheme IV: "the Cat's Cradle" (Fig.…”

Section: Ca V 12 Activation Properties Can Be Accounted For By An Almentioning

confidence: 99%

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Functional heterogeneity of the four voltage sensors of a human L-type calcium channel

Pantazis¹,

Savalli²,

Sigg³

et al. 2014

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

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107

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Excitation-evoked Ca2+ influx is the fastest and most ubiquitous chemical trigger for cellular processes, including neurotransmitter release, muscle contraction, and gene expression. The voltage dependence and timing of Ca 2+ entry are thought to be functions of voltage-gated calcium (Ca V ) channels composed of a central pore regulated by four nonidentical voltage-sensing domains (VSDs I-IV). Currently, the individual voltage dependence and the contribution to pore opening of each VSD remain largely unknown. Using an optical approach (voltage-clamp fluorometry) to track the movement of the individual voltage sensors, we discovered that the four VSDs of Ca V 1.2 channels undergo voltage-evoked conformational rearrangements, each exhibiting distinct voltage-and time-dependent properties over a wide range of potentials and kinetics. The voltage dependence and fast kinetic components in the activation of VSDs II and III were compatible with the ionic current properties, suggesting that these voltage sensors are involved in Ca V 1.2 activation. This view is supported by an obligatory model, in which activation of VSDs II and III is necessary to open the pore. When these data were interpreted in view of an allosteric model, where pore opening is intrinsically independent but biased by VSD activation, VSDs II and III were each found to supply ∼50 meV (∼2 kT), amounting to ∼85% of the total energy, toward stabilizing the open state, with a smaller contribution from VSD I (∼16 meV). VSD IV did not appear to participate in channel opening. ] regulates such critical physiological functions as neurotransmitter and hormone release, axonal outgrowth, muscle contraction, and gene expression (1). Their relevance to human physiology is evident from the broad phenotypic consequences of Ca V channelopathies (2). The voltage dependence of Ca V -driven Ca 2+ entry relies on the modular organization of the channel-forming α 1 subunit (Fig. 1), which consists of four repeated motifs (I-IV), each comprising six membrane-spanning helical segments (S1-S6) (Fig. 1A). Segments S1-S4 form a voltage-sensing domain (VSD), whereas segments S5 and S6 contribute to the Ca 2+ -conductive pore (1). The VSDs surround the central pore (Fig. 1B). VSDs are structurally and functionally conserved modules (3-5) capable of transducing a change in the cell membrane electrical potential into a change of ion-specific permeability or enzyme activity. VSDs sense depolarization by virtue of a signature motif of positively charged Arg or Lys at every third position of helix S4 (Fig. 1D), which rearranges in response to depolarization (4, 6-10). In contrast to voltage-gated K + (K V ) channels but similar to pseudotetrameric voltage-gated Na + (Na V ) channels, the amino acid sequences encoding each VSD have evolved independently (Fig. 1D). In addition to their distinct primary structure, the four Ca V VSDs may also gain distinct functional properties from the asymmetrical association of auxiliary subunits, such as β, α 2 δ, and calmodulin (1,(11)(12)(13)(14)(...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Ca V 12 Activation Properties Can Be Accounted For By An Almentioning

confidence: 99%

See 1 more Smart Citation

Functional heterogeneity of the four voltage sensors of a human L-type calcium channel

Pantazis¹,

Savalli²,

Sigg³

et al. 2014

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

Self Cite

107

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“…Although the HA model omits some aspects of the channel gating (see Refs. 26,130), the general concept is well supported by the experimental evidence, and the model has proven to be immensely useful as the conceptual framework to appreciate and analyze BK channel gating, for example, in studies of various auxiliary subunits, critical amino-acid residues, and modulators. Additionally, the formulation of the HA model largely reflects the physical organization of the BK channel protein, incorporating the consensus notion that proteins including the BK channel are made in a modular manner, whereby separate structural domains make distinct functional contributions, which are propagated through interdomain allosteric interactions.…”

Section: Allosteric Activation By Ca 2؉ and Membrane Depolarizationmentioning

confidence: 98%

Transduction of Voltage and Ca²⁺Signals by Slo1 BK Channels

2013

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Large-conductance Ca2+ -and voltage-gated K+ channels are activated by an increase in intracellular Ca2+ concentration and/or depolarization. The channel activation mechanism is well described by an allosteric model encompassing the gate, voltage sensors, and Ca2+ sensors, and the model is an excellent framework to understand the influences of auxiliary β and γ subunits and regulatory factors such as Mg2+. Recent advances permit elucidation of structural correlates of the biophysical mechanism.

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“…In contrast, mutation of calcium-sensing residue D362 in RCK1 had no effect. Thus, VCF was able to resolve conformational changes associated with the calcium binding which are transmitted through allosteric interplay to the S4 (Savalli et al, 2012). Co-expression with accessory b subunits (b1 to b4) alters the ionic current kinetics and pharmacological profile of BK Ca channels (Torres et al, 2014).…”

Section: Large Conductance Voltage-and Calcium-activated Potassium Chmentioning

confidence: 99%

Investigating ion channel conformational changes using voltage clamp fluorometry

Talwar

Lynch

2015

Neuropharmacology

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The Contribution of RCK Domains to Human BK Channel Allosteric Activation

Cited by 39 publications

References 67 publications

Functional heterogeneity of the four voltage sensors of a human L-type calcium channel

Functional heterogeneity of the four voltage sensors of a human L-type calcium channel

Transduction of Voltage and Ca²⁺Signals by Slo1 BK Channels

Investigating ion channel conformational changes using voltage clamp fluorometry

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The Contribution of RCK Domains to Human BK Channel Allosteric Activation

Cited by 39 publications

References 67 publications

Functional heterogeneity of the four voltage sensors of a human L-type calcium channel

Functional heterogeneity of the four voltage sensors of a human L-type calcium channel

Transduction of Voltage and Ca2+Signals by Slo1 BK Channels

Investigating ion channel conformational changes using voltage clamp fluorometry

Contact Info

Product

Resources

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Transduction of Voltage and Ca²⁺Signals by Slo1 BK Channels