Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt IKS regulation by PKA and PIP2

Meidan Dvir, Roi Strulovich, Dana Sachyani, Inbal Ben Tal Cohen, Yoni Haitin, Carmen Dessauer, Olaf Pongs, Robert Kass, Joel A. Hirsch, Bernard Attali*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

KCNQ1 and KCNE1 co-assembly generates the IKS K+ current, which is crucial to the cardiac action potential repolarization. Mutations in their corresponding genes cause long QT syndrome (LQT) and atrial fibrillation. The A-kinase anchor protein, yotiao (also known as AKAP9), brings the IKS channel complex together with signaling proteins to achieve regulation upon β1-adrenergic stimulation. Recently, we have shown that KCNQ1 helix C interacts with the KCNE1 distal C-terminus. We postulated that this interface is crucial for IKS channel modulation. Here, we examined the yet unknown molecular mechanisms of LQT mutations located at this intracellular intersubunit interface. All LQT mutations disrupted the internal KCNQ1-KCNE1 intersubunit interaction. LQT mutants in KCNQ1 helix C led to a decreased current density and a depolarizing shift of channel activation, mainly arising from impaired phosphatidylinositol-4,5-bisphosphate (PIP2) modulation. In the KCNE1 distal C-terminus, the LQT mutation P127T suppressed yotiao-dependent cAMP-mediated upregulation of the IKS current, which was caused by reduced KCNQ1 phosphorylation at S27. Thus, KCNQ1 helix C is important for channel modulation by PIP2, whereas the KCNE1 distal C-terminus appears essential for the regulation of IKS by yotiao-mediated PKA phosphorylation.

Original languageEnglish
Pages (from-to)3943-3955
Number of pages13
JournalJournal of Cell Science
Volume127
Issue number18
DOIs
StatePublished - 2014

Funding

FundersFunder number
National Institute of General Medical SciencesR01GM060419

    Keywords

    • Arrhythmia
    • I
    • KCNE
    • KCNQ
    • Long QT
    • Potassium channel

    Fingerprint

    Dive into the research topics of 'Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt IKS regulation by PKA and PIP2'. Together they form a unique fingerprint.

    Cite this