Large conductance Ca2+-activated K+ (BK) channel: Activation by Ca2+ and voltage

Latorre, Ramón; Brauchi, Sebastián

doi:10.4067/s0716-97602006000300003

Cited by 140 publications

(111 citation statements)

References 80 publications

(77 reference statements)

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“…4D), suggesting at least two Ca 2ϩ -binding sites and positive cooperativity. This apparent Ca 2ϩ affinity is relevant to BK channel activation (4,54). K11 ⁄ 2 likely relates to Ca 2ϩ binding to the RCK2 domain at the calcium bowl site, whereas the higher K21 ⁄ 2 value likely reflects Ca 2ϩ binding to the RCK1 domain, which has a lower apparent affinity in solution (33,47), also inferred from electrophysiological investigations (34 -37).…”

Section: Structural Organization Of the Bk Gating Ring In Solution-mentioning

confidence: 99%

Metal-driven Operation of the Human Large-conductance Voltage- and Ca2+-dependent Potassium Channel (BK) Gating Ring Apparatus

Javaherian

Yusifov

Pantazis

et al. 2011

Journal of Biological Chemistry

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Large-conductance voltage-and Ca2؉ -dependent K ؉ (BK, also known as MaxiK) channels are homo-tetrameric proteins with a broad expression pattern that potently regulate cellular excitability and Ca 2؉ homeostasis. Their activation results from the complex synergy between the transmembrane voltage sensors and a large (>300 kDa) C-terminal, cytoplasmic complex (the "gating ring"), which confers sensitivity to intracellular Ca 2؉ and other ligands. However, the molecular and biophysical operation of the gating ring remains unclear. We have used spectroscopic and particle-scale optical approaches to probe the metal-sensing properties of the human BK gating ring under physiologically relevant conditions. This functional molecular sensor undergoes Ca 2؉ -and Mg 2؉ -dependent conformational changes at physiologically relevant concentrations, detected by time-resolved and steady-state fluorescence spectroscopy. The lack of detectable Ba 2؉ -evoked structural changes defined the metal selectivity of the gating ring. Neutralization of a highaffinity Ca 2؉ -binding site (the "calcium bowl") reduced the Ca 2؉ and abolished the Mg 2؉ dependence of structural rearrangements. In congruence with electrophysiological investigations, these findings provide biochemical evidence that the gating ring possesses an additional high-affinity Ca 2؉ -binding site and that Mg 2؉ can bind to the calcium bowl with less affinity than Ca 2؉ . Dynamic light scattering analysis revealed a reversible Ca 2؉ -dependent decrease of the hydrodynamic radius of the gating ring, consistent with a more compact overall shape. These structural changes, resolved under physiologically relevant conditions, likely represent the molecular transitions that initiate the ligand-induced activation of the human BK channel.The large-conductance voltage-and Ca 2ϩ -activated K ϩ channel (BK, 4 MaxiK, Slo1) is an important regulator of cellular function including cellular excitability, neurotransmitter release, vascular tone, and hair cell tuning (1-8). Its K ϩ conductance of ϳ250 picosiemens is an order of magnitude larger than that observed in typical voltage-gated K ϩ -selective channels (9), making the BK channel a powerful regulator of the cell membrane potential. A functional BK channel is composed of four identical ␣ subunits, each consisting of a short extracellular N-terminal tail, seven transmembrane segments (S0 -S6) (10, 11), and a large intracellular C-terminal domain. The four ␣ subunits likely assemble around a central symmetry axis, forming the K ϩ -selective pore, surrounded by peripheral transmembrane voltage-sensing domains (12, 13) that undergo conformational rearrangements upon membrane depolarization (14 -16) to facilitate pore opening (17)(18)(19)(20). Another pathway to BK channel activation is mediated by intracellular Ca 2ϩ . In the CNS, BK channels localize within Ca 2ϩ nanodomains generated at the immediate proximity of voltage-gated Ca 2ϩ channels as an efficient strategy to regulate BK channel activity (reviewed by Ref. 21). Intracellular C...

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Section: Structural Organization Of the Bk Gating Ring In Solution-mentioning

confidence: 99%

Metal-driven Operation of the Human Large-conductance Voltage- and Ca2+-dependent Potassium Channel (BK) Gating Ring Apparatus

Javaherian

Yusifov

Pantazis

et al. 2011

Journal of Biological Chemistry

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“…A homology model of the Slo1 RCK1 domain based on an MthK structure 7 suggests that the two histidine residues critical for the pH i sensitivity, His365 and His394, may be in close proximity of the negatively-charged residues Asp362, Asp367, Asp369, Asp370, Glu374, Glu399, and Asp420 (Fig. 5a).…”

Section: Asp367 In the Rck1 Ca 2+ Sensor Is Important For The Ph I Sementioning

confidence: 99%

Reciprocal regulation of the Ca2+ and H+ sensitivity in the SLO1 BK channel conferred by the RCK1 domain

Hou

Heinemann

et al. 2008

Nat Struct Mol Biol

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Increasing evidence suggests that intracellular H + directly stimulates large-conductance Ca 2+ -and voltage-activated K + (Slo1 BK) channels, thus providing a crucial link between membrane excitability and cell metabolism. Here we report that two histidine residues, His365 and His394, located in the intracellular RCK1 domain serve as the H + sensors of the Slo1 BK channel. Activation of the channel by H + requires electrostatic interactions between the histidine residues and a nearby negatively charged residue involved in the channel's high-affinity Ca 2+ sensitivity. Reciprocally, His365 and His394 also participate in the Ca 2+ -dependent activation of the channel, functioning as Ca 2+ mimetics once protonated. Therefore, a common motif in the RCK1 domain mediates the stimulatory effects of both H + and Ca 2+ , and provides a basis for the bidirectional coupling of cell metabolism and membrane electrical excitability.Normal functions of excitable cells, such as neurons and muscle cells, critically depend on an intimate and finely tuned regulation of membrane excitability by the cellular metabolic state. The metabolism, in turn, is reciprocally influenced by homeostasis of intracellular ions, and dysregulation of the ion concentrations accompanies many forms of abnormal excitability such as excitoxicity following ischemia/hypoxia 1 and also in neurodegenerative diseases 2 . Among the intracellular ion species, Ca 2+ and H + are particularly important, functioning in an intertwined manner; H + can interfere with numerous Ca 2+ -dependent processes and alters the intracellular Ca 2+ concentration ([Ca 2+ ] i ) [3][4][5] in turn, alterations in [Ca 2+ ] i modulate the intracellular H + homeostasis 6 .One of the key coupling mechanisms between the cellular metabolism and electrical excitability is the Slo1 (also known as KCNMA1) BK channel 7, 8. The two distinguishing features of the channel, large conductance and synergic activation by membrane depolarization and intracellular Ca 2+ , allow the channel to exert a negative feedback influence on cellular excitability under many physiological conditions, especially in neurons and muscle cells 9 . Consistent with this functional role, opening of BK channels often plays a cell-protective role against excitoxicity following hypoxia/ischemic insults 10,11 .As in other voltage-gated K + channels, four pore-forming Slo1 subunits form a functional BK channel complex, frequently with up to four auxiliary β subunits in a tissue-specific manner 12 . The transmembrane segments with its N-terminus facing the extracellular side contain the * To whom correspondence should be addressed. E-mail: hoshi@hoshi.org. Intracellular H + is also a potent modulator of BK channel function [22][23][24] . While some conflicting reports exist whether native BK channels are stimulated or inhibited by a decrease in intracellular pH (pH i ), recent evidence shows that, unlike most other K + channels, Slo1 BK channels measured under defined conditions are robustly activated by a decrease ...

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“…Each α subunit possesses an extracellular N terminus (12), seven transmembrane segments (S0-S6), and a large intracellular C-terminal region organized into domains RCK1 and RCK2 (Regulator of Conductance for K + , Fig. 1A) that confer sensitivity to Ca 2+ and other intracellular ligands (8,9,(13)(14)(15)(16)(17)(18)(19)(20). Segments S1-S6 are structurally and functionally homologous to those of other voltage-gated ion channels (21), with S1-S4 comprising the VSD, whereas S5 and S6 contribute to the K + -selective pore.…”

mentioning

confidence: 99%

“…Their activation, by membrane potential depolarization or intracellular [Ca 2+ ] increase (1-9) results in an exceptionally high conductance for K + . As such, they are potent regulators of diverse cellular processes, including smooth muscle tone, neuronal excitability, and neurotransmitter release (8). Four pore-forming α subunits (10), encoded by KCNMA1 (hSlo1) in humans (11), are required to assemble into a functional channel.…”

mentioning

confidence: 99%

Operation of the voltage sensor of a human voltage- and Ca ²⁺ -activated K ⁺ channel

Pantazis

Gudzenko²,

Savalli³

et al. 2010

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

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Voltage sensor domains (VSDs) are structurally and functionally conserved protein modules that consist of four transmembrane segments (S1-S4) and confer voltage sensitivity to many ion channels. Depolarization is sensed by VSD-charged residues residing in the membrane field, inducing VSD activation that facilitates channel gating. S4 is typically thought to be the principal functional component of the VSD because it carries, in most channels, a large portion of the VSD gating charge. The VSDs of large-conductance, voltage-and Ca 2+ -activated K + channels are peculiar in that more gating charge is carried by transmembrane segments other than S4. Considering its "decentralized" distribution of voltage-sensing residues, we probed the BK Ca VSD for evidence of cooperativity between charge-carrying segments S2 and S4. We achieved this by optically tracking their activation by using voltage clamp fluorometry, in channels with intact voltage sensors and charge-neutralized mutants. The results from these experiments indicate that S2 and S4 possess distinct voltage dependence, but functionally interact, such that the effective valence of one segment is affected by charge neutralization in the other. Statisticalmechanical modeling of the experimental findings using allosteric interactions demonstrates two mechanisms (mechanical coupling and dynamic focusing of the membrane electric field) that are compatible with the observed cross-segment effects of charge neutralization. increase (1-9) results in an exceptionally high conductance for K + . As such, they are potent regulators of diverse cellular processes, including smooth muscle tone, neuronal excitability, and neurotransmitter release (8). Four pore-forming α subunits (10), encoded by KCNMA1 (hSlo1) in humans (11), are required to assemble into a functional channel. Each α subunit possesses an extracellular N terminus (12), seven transmembrane segments (S0-S6), and a large intracellular C-terminal region organized into domains RCK1 and RCK2 (Regulator of Conductance for K + , Fig. 1A) that confer sensitivity to Ca 2+ and other intracellular ligands (8,9,(13)(14)(15)(16)(17)(18)(19)(20). Segments S1-S6 are structurally and functionally homologous to those of other voltage-gated ion channels (21), with S1-S4 comprising the VSD, whereas S5 and S6 contribute to the K + -selective pore.Our understanding of VSD structure and function has been achieved thus far through analysis of crystal structures (22-24) as well as accessibility, electrophysiological, and optical investigations in functional proteins (reviewed in ref. 25). VSDs possess a high density of charged residues (Fig. 1C). Upon membrane potential depolarization, a subset of these residues may traverse the field partially or entirely, initiating conformational rearrangements that propagate to the channel gate, facilitating ionic conductance (26-28). S4 is thought to be the principal voltagesensing segment because, in most VSD-gated channels, it contributes the greatest portion of gating charge movement (29-31). S2 ...

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Large conductance Ca2+-activated K+ (BK) channel: Activation by Ca2+ and voltage

Cited by 140 publications

References 80 publications

Metal-driven Operation of the Human Large-conductance Voltage- and Ca2+-dependent Potassium Channel (BK) Gating Ring Apparatus

Metal-driven Operation of the Human Large-conductance Voltage- and Ca2+-dependent Potassium Channel (BK) Gating Ring Apparatus

Reciprocal regulation of the Ca2+ and H+ sensitivity in the SLO1 BK channel conferred by the RCK1 domain

Operation of the voltage sensor of a human voltage- and Ca ²⁺ -activated K ⁺ channel

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Large conductance Ca2+-activated K+ (BK) channel: Activation by Ca2+ and voltage

Cited by 140 publications

References 80 publications

Metal-driven Operation of the Human Large-conductance Voltage- and Ca2+-dependent Potassium Channel (BK) Gating Ring Apparatus

Metal-driven Operation of the Human Large-conductance Voltage- and Ca2+-dependent Potassium Channel (BK) Gating Ring Apparatus

Reciprocal regulation of the Ca2+ and H+ sensitivity in the SLO1 BK channel conferred by the RCK1 domain

Operation of the voltage sensor of a human voltage- and Ca 2+ -activated K + channel

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Operation of the voltage sensor of a human voltage- and Ca ²⁺ -activated K ⁺ channel