(R)-L3 activates Kv7.1 channels and alters their kinetics by interacting with key residues in the lower S4-segment, leading to an electro-mechanical uncoupling of the outer S4 segment from the inner pore domains.
The study elucidates the molecular mechanism by which (R)-L3 activates Kv7.1 channels, providing a potential structural basis for developing new pharmacological treatments for long QT syndrome.
Abstract Loss-of-function mutations in K v 7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic I Ks modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative ( R )-L3 potently activates K v 7.1 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 K v 7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.
Schreiber et al. (Fri,) conducted a other in Long QT syndrome (LQTS) / Kv7.1 channel dysfunction. (R)-L3 vs. Control solution (absence of (R)-L3) was evaluated on Kv7.1 channel activation and kinetics. (R)-L3 activates Kv7.1 channels and alters their kinetics by interacting with key residues in the lower S4-segment, leading to an electro-mechanical uncoupling of the outer S4 segment from the inner pore domains.