Interactions between hERG and KCNQ1 α-subunits are mediated by their COOH termini and modulated by cAMP

Louise E. Organ-Darling, Amanda N. Vernon, Jacqueline R. Giovanniello, Yichun Lu, Karni Moshal, Karim Roder, Weiyan Li, Gideon Koren

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

KCNQ1 and hERG encode the voltage-gated potassium channel α-subunits of the cardiac repolarizing currents IKs and IKr, respectively. These currents function in vivo with some redundancy to maintain appropriate action potential durations (APDs), and loss-of-function mutations in these channels manifest clinically as long QT syndrome, characterized by the prolongation of the QT interval, polymorphic ventricular tachycardia, and sudden cardiac death. Previous cellular electrophysiology experiments in transgenic rabbit cardiomyocytes and heterologous cell lines demonstrated functional downregulation of complementary repolarizing currents. Biochemical assays indicated direct, protein-protein interactions between KCNQ1 and hERG may underlie the interplay between IKs and IKr. Our objective was to investigate hERG-KCNQ1 interactions in the intact cellular environment primarily through acceptor photobleach FRET (apFRET) experiments. We quantitatively assessed the extent of interactions based on fluorophore location and the potential regulation of interactions by physiologically relevant signals. apFRET experiments established specific hERG-KCNQ1 associations in both heterologous and primary cardiomyocytes. The largest FRET efficiency (Ef; 12.0 ± 5.2%) was seen between ion channels with GFP variants fused to the COOH termini. Acute treatment with forskolin + IBMX or a membrane-permeable cAMP analog significantly and specifically reduced the extent of hERG-KCNQ1 interactions (by 41 and 38%, respectively). Our results demonstrate direct interactions between KCNQ1 and hERG occur in both intact heterologous cells and primary cardiomyocytes and are mediated by their COOH termini. Furthermore, this interplay between channel proteins is regulated by intracellular cAMP.

Original languageEnglish
Pages (from-to)H589-H599
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number4
DOIs
StatePublished - 15 Feb 2013
Externally publishedYes

Keywords

  • Arrhythmia
  • FRET
  • Potassium channel
  • Repolarization reserve

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