ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31329101.
- Also identified by DOI 10.7554/eLife.48576 and PMC identifier 6684268.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form I<sub>Ks</sub> channels that regulate heart rhythm. KCNE1 suppresses the IO state so that the I<sub>Ks</sub> channel opens only to the AO state. Here, we tested modulations of human KCNQ1 channels by an activator ML277 in <i>Xenopus</i> oocytes. It exclusively changes the pore opening properties of the AO state without altering the IO state, but does not affect VSD activation. These observations support a distinctive mechanism responsible for the VSD-pore coupling at the AO state that is sensitive to ML277 modulation. ML277 provides insights and a tool to investigate the gating mechanism of KCNQ1 channels, and our study reveals a new strategy for treating long QT syndrome by specifically enhancing the AO state of native I<sub>Ks</sub> currents.
Medical subject headings
- KCNQ1 Potassium Channel
- Long QT Syndrome
- Potassium Channels, Voltage-Gated