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