A benzodiazepine activator locks Kv7.1 channels open by electro-mechanical uncoupling

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Standard

A benzodiazepine activator locks Kv7.1 channels open by electro-mechanical uncoupling. / Schreiber, Julian A.; Möller, Melina; Zaydman, Mark; Zhao, Lu; Beller, Zachary; Becker, Sebastian; Ritter, Nadine; Hou, Panpan; Shi, Jingyi; Silva, Jon; Wrobel, Eva; Strutz-Seebohm, Nathalie; Decher, Niels; Schmitt, Nicole; Meuth, Sven G.; Düfer, Martina; Wünsch, Bernhard; Cui, Jianmin; Seebohm, Guiscard.

I: Communications Biology , Bind 5, Nr. 1, 301, 2022, s. 1-13.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

Schreiber, JA, Möller, M, Zaydman, M, Zhao, L, Beller, Z, Becker, S, Ritter, N, Hou, P, Shi, J, Silva, J, Wrobel, E, Strutz-Seebohm, N, Decher, N, Schmitt, N, Meuth, SG, Düfer, M, Wünsch, B, Cui, J & Seebohm, G 2022, 'A benzodiazepine activator locks Kv7.1 channels open by electro-mechanical uncoupling', Communications Biology , bind 5, nr. 1, 301, s. 1-13. https://doi.org/10.1038/s42003-022-03229-8

APA

Schreiber, J. A., Möller, M., Zaydman, M., Zhao, L., Beller, Z., Becker, S., Ritter, N., Hou, P., Shi, J., Silva, J., Wrobel, E., Strutz-Seebohm, N., Decher, N., Schmitt, N., Meuth, S. G., Düfer, M., Wünsch, B., Cui, J., & Seebohm, G. (2022). A benzodiazepine activator locks Kv7.1 channels open by electro-mechanical uncoupling. Communications Biology , 5(1), 1-13. [301]. https://doi.org/10.1038/s42003-022-03229-8

Vancouver

Schreiber JA, Möller M, Zaydman M, Zhao L, Beller Z, Becker S o.a. A benzodiazepine activator locks Kv7.1 channels open by electro-mechanical uncoupling. Communications Biology . 2022;5(1):1-13. 301. https://doi.org/10.1038/s42003-022-03229-8

Author

Schreiber, Julian A. ; Möller, Melina ; Zaydman, Mark ; Zhao, Lu ; Beller, Zachary ; Becker, Sebastian ; Ritter, Nadine ; Hou, Panpan ; Shi, Jingyi ; Silva, Jon ; Wrobel, Eva ; Strutz-Seebohm, Nathalie ; Decher, Niels ; Schmitt, Nicole ; Meuth, Sven G. ; Düfer, Martina ; Wünsch, Bernhard ; Cui, Jianmin ; Seebohm, Guiscard. / A benzodiazepine activator locks Kv7.1 channels open by electro-mechanical uncoupling. I: Communications Biology . 2022 ; Bind 5, Nr. 1. s. 1-13.

Bibtex

@article{7a91edfda98f43dcb6dc6b559967bcc3,
title = "A benzodiazepine activator locks Kv7.1 channels open by electro-mechanical uncoupling",
abstract = "Loss-of-function mutations in Kv7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic IKs modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative (R)-L3 potently activates Kv7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by (R)-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we show that (R)-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identify novel (R)-L3-interacting key residues in the lower S4-segment of Kv7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.",
author = "Schreiber, {Julian A.} and Melina M{\"o}ller and Mark Zaydman and Lu Zhao and Zachary Beller and Sebastian Becker and Nadine Ritter and Panpan Hou and Jingyi Shi and Jon Silva and Eva Wrobel and Nathalie Strutz-Seebohm and Niels Decher and Nicole Schmitt and Meuth, {Sven G.} and Martina D{\"u}fer and Bernhard W{\"u}nsch and Jianmin Cui and Guiscard Seebohm",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
doi = "10.1038/s42003-022-03229-8",
language = "English",
volume = "5",
pages = "1--13",
journal = "Communications Biology",
issn = "2399-3642",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - A benzodiazepine activator locks Kv7.1 channels open by electro-mechanical uncoupling

AU - Schreiber, Julian A.

AU - Möller, Melina

AU - Zaydman, Mark

AU - Zhao, Lu

AU - Beller, Zachary

AU - Becker, Sebastian

AU - Ritter, Nadine

AU - Hou, Panpan

AU - Shi, Jingyi

AU - Silva, Jon

AU - Wrobel, Eva

AU - Strutz-Seebohm, Nathalie

AU - Decher, Niels

AU - Schmitt, Nicole

AU - Meuth, Sven G.

AU - Düfer, Martina

AU - Wünsch, Bernhard

AU - Cui, Jianmin

AU - Seebohm, Guiscard

N1 - Publisher Copyright: © 2022, The Author(s).

PY - 2022

Y1 - 2022

N2 - Loss-of-function mutations in Kv7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic IKs modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative (R)-L3 potently activates Kv7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by (R)-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we show that (R)-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identify novel (R)-L3-interacting key residues in the lower S4-segment of Kv7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.

AB - Loss-of-function mutations in Kv7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic IKs modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative (R)-L3 potently activates Kv7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by (R)-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we show that (R)-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identify novel (R)-L3-interacting key residues in the lower S4-segment of Kv7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.

UR - http://www.scopus.com/inward/record.url?scp=85127456321&partnerID=8YFLogxK

U2 - 10.1038/s42003-022-03229-8

DO - 10.1038/s42003-022-03229-8

M3 - Journal article

C2 - 35365746

AN - SCOPUS:85127456321

VL - 5

SP - 1

EP - 13

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

IS - 1

M1 - 301

ER -

ID: 310848881