Mode Shift of the Voltage Sensors in Shaker K+ Channels is Caused by Energetic Coupling to the Pore Domain

Haddad, Georges A.; Blunck, Rikard

doi:10.1016/j.bpj.2010.12.2191

Cited by 14 publications

(30 citation statements)

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“…Moreover, a noninactivating mutant of the human ether-a-go-go related gene (HERG) channel (20) and noninactivating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (21) both show holding-potential-dependent shifts in Q-V curves. Finally, this correlation between charge shift and C-type inactivation has been reexamined by other groups who have concluded that these two processes are not coupled in the Shaker potassium channel (22).…”

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confidence: 67%

Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor

Capes

Arcísio-Miranda

Jarecki

et al. 2012

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

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Voltage-dependent ion channels are crucial for generation and propagation of electrical activity in biological systems. The primary mechanism for voltage transduction in these proteins involves the movement of a voltage-sensing domain (D), which opens a gate located on the cytoplasmic side. A distinct conformational change in the selectivity filter near the extracellular side has been implicated in slow inactivation gating, which is important for spike frequency adaptation in neural circuits. However, it remains an open question whether gating transitions in the selectivity filter region are also actuated by voltage sensors. Here, we examine conformational coupling between each of the four voltage sensors and the outer pore of a eukaryotic voltage-dependent sodium channel. The voltage sensors of these sodium channels are not structurally symmetric and exhibit functional specialization. To track the conformational rearrangements of individual voltagesensing domains, we recorded domain-specific gating pore currents. Our data show that, of the four voltage sensors, only the domain IV voltage sensor is coupled to the conformation of the selectivity filter region of the sodium channel. Trapping the outer pore in a particular conformation with a high-affinity toxin or disulphide crossbridge impedes the return of this voltage sensor to its resting conformation. Our findings directly establish that, in addition to the canonical electromechanical coupling between voltage sensor and inner pore gates of a sodium channel, gating transitions in the selectivity filter region are also coupled to the movement of a voltage sensor. Furthermore, our results also imply that the voltage sensor of domain IV is unique in this linkage and in the ability to initiate slow inactivation in sodium channels. electrophysiology | Nav1.4 | outer pore conformation

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mentioning

confidence: 67%

Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor

Capes

Arcísio-Miranda

Jarecki

et al. 2012

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

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“…3C). The interaction is mediated by annealing of the S4-S5 linker to the C-terminal end of S6 (S6T (9,10,11,13,14,51)). The S4-S5 linker "presses" against the S6 at the level of its PVP motif, and accordingly, the pore closes with a "hydrophobic seal" by pushing the isoleucine 398 residues into the pathway, excluding most water molecules from the central cavity in the closed state (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Limited 4 Å Radial Displacement of the S4-S5 Linker Is Sufficient for Internal Gate Closing in Kv Channels

Faure

Starek

McGuire

et al. 2012

Journal of Biological Chemistry

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“…In support of this idea, voltage sensor relaxation in Shaker is also sensitive to both the length and composition of the S3-S4 linker (22). Other studies have shown that mutations in the S4-S5 linker and S6 of Shaker channels, which uncouple the voltage sensor from the pore gate, also impede mode-shift behavior, suggesting that mode-shift might originate from the mechanical load placed on the voltage sensor domain by the pore (23,24). Others have also suggested that voltage-independent gating steps might underlie mode-shift behavior, rather than voltage sensor-mediated relaxation (25).…”

Section: Introductionmentioning

confidence: 87%

“…We were further driven to investigate the S4-S5 linker by the observation that disruption of the physical connection between the voltage sensor and pore domains, while not influencing activation greatly, impacted deactivation gating significantly (7). Furthermore, evidence from Shaker channels suggests that the S4-S5 linker couples the pore and voltage sensor during deactivation based on the observation that specific interactions between residues in the S4-S5 linker and the pore control mode-shift behavior (24). Fig.…”

Section: S4-s5 Linker Coupling During Deactivationmentioning

confidence: 99%

Stabilization of the Activated hERG Channel Voltage Sensor by Depolarization Involves the S4-S5 Linker

Thouta

Hull

Shi

et al. 2017

Biophysical Journal

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Slow deactivation of hERG channels is critical for preventing cardiac arrhythmia yet the mechanistic basis for the slow gating transition is unclear. Here, we characterized the temporal sequence of events leading to voltage sensor stabilization upon membrane depolarization. Progressive increase in step depolarization duration slowed voltage-sensor return in a biphasic manner (t fast ¼ 34 ms, t slow ¼ 2.5 s). The faster phase of voltage-sensor return slowing correlated with the kinetics of pore opening. The slower component occurred over durations that exceeded channel activation and was consistent with voltage sensor relaxation. The S4-S5 linker mutation, G546L, impeded the faster phase of voltage sensor stabilization without attenuating the slower phase, suggesting that the S4-S5 linker is important for communications between the pore gate and the voltage sensor during deactivation. These data also demonstrate that the mechanisms of pore gate-opening-induced and relaxation-induced voltage-sensor stabilization are separable. Deletion of the distal N-terminus (D2-135) accelerated off-gating current, but did not influence the relative contribution of either mechanism of stabilization of the voltage sensor. Lastly, we characterized mode-shift behavior in hERG channels, which results from stabilization of activated channel states. The apparent mode-shift depended greatly on recording conditions. By measuring slow activation and deactivation at steady state we found the ''true'' mode-shift to be~15 mV. Interestingly, the ''true'' mode-shift of gating currents was~40 mV, much greater than that of the pore gate. This demonstrates that voltage sensor return is less energetically favorable upon repolarization than pore gate closure. We interpret this to indicate that stabilization of the activated voltage sensor limits the return of hERG channels to rest. The data suggest that this stabilization occurs as a result of reconfiguration of the pore gate upon opening by a mechanism that is influenced by the S4-S5 linker, and by a separable voltage-sensor intrinsic relaxation mechanism.

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Mode Shift of the Voltage Sensors in Shaker K+ Channels is Caused by Energetic Coupling to the Pore Domain

Cited by 14 publications

References 0 publications

Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor

Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor

A Limited 4 Å Radial Displacement of the S4-S5 Linker Is Sufficient for Internal Gate Closing in Kv Channels

Stabilization of the Activated hERG Channel Voltage Sensor by Depolarization Involves the S4-S5 Linker

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