ArticlePflugers Archiv : European journal of physiology2014
Regional flexibility in the S4-S5 linker regulates hERG channel closed-state stabilization.
Article in Pflugers Archiv : European journal of physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Article
- Hysteretic hERG channel gating current recorded at physiological temperature.Scientific reports · 2022Article
- Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243.The Journal of general physiology · 2021Article
- Molecular Insights Into the Gating Kinetics of the Cardiac hERG Channel, Illuminated by Structure and Molecular Dynamics.Frontiers in pharmacology · 2021Review
- hERG Function in Light of Structure.Biophysical journal · 2020Review
- Modulation of hERG KFrontiers in pharmacology · 2020Review
- Extracellular protons accelerate hERG channel deactivation by destabilizing voltage sensor relaxation.The Journal of general physiology · 2019Article
- Gating mechanism of Kv11.1 (hERG) KPflugers Archiv : European journal of physiology · 2018Article
- Hysteresis in voltage-gated channels.Channels (Austin, Tex.) · 2017Review
- Stabilization of the Activated hERG Channel Voltage Sensor by Depolarization Involves the S4-S5 Linker.Biophysical journal · 2017Article
- Allosteric coupling between proximal C-terminus and selectivity filter is facilitated by the movement of transmembrane segment 4 in TREK-2 channel.Scientific reports · 2016Article
- Dominant negative consequences of a hERG 1b-specific mutation associated with intrauterine fetal death.Progress in biophysics and molecular biology · 2016Article
- Bimodal regulation of an Elk subfamily K+ channel by phosphatidylinositol 4,5-bisphosphate.The Journal of general physiology · 2015Article
- Conservation analysis of residues in the S4-S5 linker and the terminal part of the S5-P-S6 pore modulus in Kv and HCN channels: flexible determinants for the electromechanical coupling.Pflugers Archiv : European journal of physiology · 2015Article
- Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains.Nature communications · 2015Article
- Sequence of gating charge movement and pore gating in HERG activation and deactivation pathways.Biophysical journal · 2015Article
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4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
hERG K(+) channel function is vital for normal cardiac rhythm, yet the mechanisms underlying the unique biophysical characteristics of the channel, such as slow activation and deactivation gating, are incompletely understood. The S4-S5 linker is thought to transduce voltage sensor movement to opening of the pore gate, but may also integrate signals from cytoplasmic domains. Previously, we showed that substitutions of G546 within the S4-S5 linker destabilize the closed state of the channel. Here, we present results of a glycine-scan in the background of 546L. We demonstrate site-specific restoration of WT-like activation which suggests that flexibility in the N-terminal portion of the S4-S5 linker is critical for the voltage dependence of hERG channel activation. In addition, we show that the voltage dependence of deactivation, which was recently shown to be left-shifted from that of activation due to voltage sensor mode-shift, is also modulated by the S4-S5 linker. The G546L mutation greatly attenuated the coupling of voltage sensor mode-shift to the pore gate without altering the mode-shift itself. Indeed, all of the S4-S5 linker mutations tested similarly reduced coupling of the mode-shift to the pore gate. These data demonstrate a key role for S4-S5 linker in the unique activation and deactivation gating of hERG channels. Furthermore, uncoupling of the mode-shift to the pore by S4-S5 linker mutations parallels the effects of mutations in the N-terminus suggestive of functional interactions between the two regions.
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