Molecular Basis for the Inactivation of Ca<sup>2+</sup>- and Voltage-Dependent BK Channels in Adrenal Chromaffin Cells and Rat Insulinoma Tumor Cells

Xia, Xiaoming; Ding, Jiu; Lingle, Christopher J.

doi:10.1523/jneurosci.19-13-05255.1999

Cited by 248 publications

(439 citation statements)

References 44 publications

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“…BK channels are noninactivating K + channels, except in the presence of a β2 or β3 auxiliary subunit whose N-terminal peptide sequence occludes the channel pore in a more N-type inactivation manner (31)(32)(33). We found that, even under nearly K + -free conditions in the external recording solution, WT BK channels did not show any significant inactivation up to 10 s. The presence of Tyr at the BK channel 294 position (equivalent to the 449 position in Shaker channels) might partly contribute to the noninactivation because the T449Y mutation slows down C-type inactivation in Shaker channels (25).…”

Section: Discussionmentioning

confidence: 99%

Closed state-coupled C-type inactivation in BK channels

Yan

Aldrich

2016

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

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Ion channels regulate ion flow by opening and closing their pore gates. K + channels commonly possess two pore gates, one at the intracellular end for fast channel activation/deactivation and the other at the selectivity filter for slow C-type inactivation/recovery. The large-conductance calcium-activated potassium (BK) channel lacks a classic intracellular bundle-crossing activation gate and normally show no C-type inactivation. We hypothesized that the BK channel's activation gate may spatially overlap or coexist with the C-type inactivation gate at or near the selectivity filter. We induced C-type inactivation in BK channels and studied the relationship between activation/deactivation and C-type inactivation/ recovery. We observed prominent slow C-type inactivation/recovery in BK channels by an extreme low concentration of extracellular K + together with a Y294E/K/Q/S or Y279F mutation whose equivalent in Shaker channels (T449E/K/D/Q/S or W434F) caused a greatly accelerated rate of C-type inactivation or constitutive C-inactivation. C-type inactivation in most K + channels occurs upon sustained membrane depolarization or channel opening and then recovers during hyperpolarized membrane potentials or channel closure. However, we found that the BK channel C-type inactivation occurred during hyperpolarized membrane potentials or with decreased intracellular calcium ([Ca 2+ ] i ) and recovered with depolarized membrane potentials or elevated [Ca 2+ ] i . Constitutively open mutation prevented BK channels from C-type inactivation. We concluded that BK channel C-type inactivation is closed statedependent and that its extents and rates inversely correlate with channel-open probability. Because C-type inactivation can involve multiple conformational changes at the selectivity filter, we propose that the BK channel's normal closing may represent an early conformational stage of C-type inactivation.I on channels regulate ion flow across membranes through the voltage-or ligand-regulated opening and closing of a conformational constriction site (gate) at the central pore. For most K + channels, the pore gate located near the pore's intracellular end, called a "bundle-crossing" region, controls fast channel activation/ deactivation (1-4) whereas the existence of another pore gate at the selectivity filter controls slow C-type inactivation and recovery (1, 5-8). C-type inactivation in the widely studied voltagegated Drosophila melanogaster Shaker and mammalian Kv channels or the prokaryotic pH-gated KcsA channels is known to occur from the open state as a result of sustained membrane depolarization or acidic intracellular pH. Extensive structural studies have indicated that C-type inactivation results from changes in ion occupancy and structural rearrangements at or near the selectivity filter (1, 5-8). C-type inactivation is distinct from the fast N-type inactivation, which involves pore blockade by a positively charged N-terminal ball peptide (9, 10).The large-conductance, calcium-activated potassium (BK) channel is acti...

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Section: Discussionmentioning

confidence: 99%

Closed state-coupled C-type inactivation in BK channels

Yan

Aldrich

2016

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

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“…They are negative feedback regulators of cellular excitability and of [Ca 2ϩ ] i . BK channels are a complex of four ␣-subunits (1) and four ␤-subunits (2)(3)(4)(5)(6)(7). In addition to the S1-S6 transmembrane (TM) helices conserved in all voltage-gated K ϩ channels, ␣ contains a unique seventh TM helix, S0, N-terminal to S1-S6; furthermore, the first 19 residues preceding S0 are extracellular (Fig.…”

mentioning

confidence: 99%

Locations of the β1 transmembrane helices in the BK potassium channel

Liu¹,

Zakharov²,

Yang³

et al. 2008

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

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BK channels are composed of ␣-subunits, which form a voltageand Ca 2؉ -gated potassium channel, and of modulatory ␤-subunits. The ␤1-subunit is expressed in smooth muscle, where it renders the BK channel sensitive to [Ca 2؉ ]i in a voltage range near the smoothmuscle resting potential and slows activation and deactivation. BK channel acts thereby as a damped feedback regulator of voltagedependent Ca 2؉ channels and of smooth muscle tone. We explored the contacts between ␣ and ␤1 by determining the extent of endogenous disulfide bond formation between cysteines substituted just extracellular to the two ␤1 transmembrane (TM) helices, TM1 and TM2, and to the seven ␣ TM helices, consisting of S1-S6, conserved in all voltage-dependent potassium channels, and the unique S0 helix, which we previously concluded was partly surrounded by S1-S4. We now find that the extracellular ends of ␤1 TM2 and ␣ S0 are in contact and that ␤1 TM1 is close to both S1 and S2. The extracellular ends of TM1 and TM2 are not close to S3-S6. In almost all cases, cross-linking of TM2 to S0 or of TM1 to S1 or S2 shifted the conductance-voltage curves toward more positive potentials, slowed activation, and speeded deactivation, and in general favored the closed state. TM1 and TM2 are in position to contribute, in concert with the extracellular loop and the intracellular N-and C-terminal tails of ␤1, to the modulation of BK channel function.auxiliary subunit ͉ cysteine substitution ͉ disulfide cross-linking ͉ electrophysiology ͉ mslo1 B K potassium channels have large conductances and are uniquely both voltage-and Ca 2ϩ -activated. They are negative feedback regulators of cellular excitability and of [Ca 2ϩ ] i . BK channels are a complex of four ␣-subunits (1) and four ␤-subunits (2-7). In addition to the S1-S6 transmembrane (TM) helices conserved in all voltage-gated K ϩ channels, ␣ contains a unique seventh TM helix, S0, N-terminal to S1-S6; furthermore, the first 19 residues preceding S0 are extracellular (Fig. 1A) (8).A large cytoplasmic domain, C-terminal to S6, contains two RCK domains, resembling those of the bacterial Ca 2ϩ -gated K ϩ channel, MthK (9). The voltage-sensitivity of the BK channel is a property of the membrane domain of ␣, whereas the Ca 2ϩ -sensitivity is conferred by the C-terminal cytoplasmic domain (10).The channel formed by BK ␣ is modulated by ␤-subunits. There are four types of ␤-subunits, ␤1, ␤2, ␤3, and ␤4, 191-235 residues in length (2-6). ␤-Subunits have short cytoplasmic Nand C-terminal segments, two TM helices, TM1 and TM2, and a large extracellular loop between them (Fig. 1B). The ␤1-subunit is expressed in smooth muscle. In the presence of Ca 2ϩ , it shifts the V 50 for channel activation toward the resting potential, around which channel opening becomes a roughly linear function of [Ca 2ϩ ] i in the physiologically relevant 1-10 M range. In addition, ␤1 slows both activation and deactivation. Activation of BK channels shifts the membrane potential to more negative values, suppressing the activity of L-ty...

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“…Their binding to the channel is altered by the association of ␤ subunits; ␤1 enhances the binding affinity of ChTx (37) but reduces the sensitivity of the current to IbTx (38), whereas ␤2 and ␤4 reduce sensitivity to ChTx and IbTx inhibition (8,26). Experimental evidence suggests that these effects are mediated by the extracellular loop of the ␤ subunits that extends to the extracellular vestibule of the pore (26,37,39). Similar to ChTx and IbTx, ␤4 reduced inhibition by slotoxin (40).…”

Section: Discussionmentioning

confidence: 99%

Conopeptide Vt3.1 Preferentially Inhibits BK Potassium Channels Containing β4 Subunits via Electrostatic Interactions

Chang

Yang

et al. 2014

Journal of Biological Chemistry

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Background: BK channel function is differentially modulated by tissue-specific ␤ (␤1-4) subunits. Results: Conopeptide Vt3.1 preferentially inhibits neuronal BK channels containing the ␤4 subunit. Conclusion: Electrostatic interactions between Vt3.1 and the extracellular loop of ␤4 decrease voltage-dependent activation of the channel. Significance: Vt3.1 is an excellent tool for studying the structure, function, and roles in neurophysiology of BK channels.

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Molecular Basis for the Inactivation of Ca²⁺- and Voltage-Dependent BK Channels in Adrenal Chromaffin Cells and Rat Insulinoma Tumor Cells

Cited by 248 publications

References 44 publications

Closed state-coupled C-type inactivation in BK channels

Closed state-coupled C-type inactivation in BK channels

Locations of the β1 transmembrane helices in the BK potassium channel

Conopeptide Vt3.1 Preferentially Inhibits BK Potassium Channels Containing β4 Subunits via Electrostatic Interactions

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Molecular Basis for the Inactivation of Ca2+- and Voltage-Dependent BK Channels in Adrenal Chromaffin Cells and Rat Insulinoma Tumor Cells

Cited by 248 publications

References 44 publications

Closed state-coupled C-type inactivation in BK channels

Closed state-coupled C-type inactivation in BK channels

Locations of the β1 transmembrane helices in the BK potassium channel

Conopeptide Vt3.1 Preferentially Inhibits BK Potassium Channels Containing β4 Subunits via Electrostatic Interactions

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Molecular Basis for the Inactivation of Ca²⁺- and Voltage-Dependent BK Channels in Adrenal Chromaffin Cells and Rat Insulinoma Tumor Cells