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• W2904347857 startingPage "231" @default.
• W2904347857 abstract "hERG channels underlie the delayed-rectifier K+ channel current (IKr), which is crucial for membrane repolarization and therefore termination of the cardiac action potential. hERG channels display unusually slow deactivation gating, which contributes to a resurgent current upon repolarization and may protect against post-depolarization–induced arrhythmias. hERG channels also exhibit robust mode shift behavior, which reflects the energetic separation of activation and deactivation pathways due to voltage sensor relaxation into a stable activated state. The mechanism of relaxation is unknown and likely contributes to slow hERG channel deactivation. Here, we use extracellular acidification to probe the structural determinants of voltage sensor relaxation and its influence on the deactivation gating pathway. Using gating current recordings and voltage clamp fluorimetry measurements of voltage sensor domain dynamics, we show that voltage sensor relaxation is destabilized at pH 6.5, causing an ∼20-mV shift in the voltage dependence of deactivation. We show that the pH dependence of the resultant loss of mode shift behavior is similar to that of the deactivation kinetics acceleration, suggesting that voltage sensor relaxation correlates with slower pore gate closure. Neutralization of D509 in S3 also destabilizes the relaxed state of the voltage sensor, mimicking the effect of protons, suggesting that acidic residues on S3, which act as countercharges to S4 basic residues, are involved in stabilizing the relaxed state and slowing deactivation kinetics. Our findings identify the mechanistic determinants of voltage sensor relaxation and define the long-sought mechanism by which protons accelerate hERG deactivation." @default.
• W2904347857 created "2018-12-22" @default.
• W2904347857 creator A5025356114 @default.
• W2904347857 creator A5045583699 @default.
• W2904347857 creator A5070954234 @default.
• W2904347857 creator A5087088567 @default.
• W2904347857 date "2018-12-07" @default.
• W2904347857 modified "2023-09-26" @default.
• W2904347857 title "Extracellular protons accelerate hERG channel deactivation by destabilizing voltage sensor relaxation" @default.
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• W2904347857 doi "https://doi.org/10.1085/jgp.201812137" @default.
• W2904347857 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6363419" @default.
• W2904347857 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30530765" @default.
• W2904347857 hasPublicationYear "2018" @default.
• W2904347857 type Work @default.
• W2904347857 sameAs 2904347857 @default.

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