Hyperphosphorylation of RyRs underlies triggered activity in transgenic rabbit model of LQT2 syndrome

Dmitry Terentyev, Colin M. Rees, Weiyan Li, Leroy L. Cooper, Hitesh K. Jindal, Xuwen Peng, Yichun Lu, Radmila Terentyeva, Katja E. Odening, Jean Daley, Kamana Bist, Bum Rak Choi, Alain Karma, Gideon Koren

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Rationale: Loss-of-function mutations in human ether go-go (HERG) potassium channels underlie long QT syndrome type 2 (LQT2) and are associated with fatal ventricular tachyarrhythmia. Previously, most studies focused on plasma membrane-related pathways involved in arrhythmogenesis in long QT syndrome, whereas proarrhythmic changes in intracellular Ca2+ handling remained unexplored. Objective: We investigated the remodeling of Ca2+ homeostasis in ventricular cardiomyocytes derived from transgenic rabbit model of LQT2 to determine whether these changes contribute to triggered activity in the form of early after depolarizations (EADs). Methods and Results: Confocal Ca2+ imaging revealed decrease in amplitude of Ca2+ transients and sarcoplasmic reticulum Ca2+ content in LQT2 myocytes. Experiments using sarcoplasmic reticulum-entrapped Ca2+ indicator demonstrated enhanced ryanodine receptor (RyR)-mediated sarcoplasmic reticulum Ca2+ leak in LQT2 cells. Western blot analyses showed increased phosphorylation of RyR in LQT2 myocytes versus controls. Coimmunoprecipitation experiments demonstrated loss of protein phosphatases type 1 and type 2 from the RyR complex. Stimulation of LQT2 cells with β-adrenergic agonist isoproterenol resulted in prolongation of the plateau of action potentials accompanied by aberrant Ca2+ releases and EADs, which were abolished by inhibition of Ca2+/calmodulin-dependent protein kinase type 2. Computer simulations showed that late aberrant Ca2+ releases caused by RyR hyperactivity promote EADs and underlie the enhanced triggered activity through increased forward mode of Na+/Ca2+ exchanger type 1. Conclusions: Hyperactive, hyperphosphorylated RyRs because of reduced local phosphatase activity enhance triggered activity in LQT2 syndrome. EADs are promoted by aberrant RyR-mediated Ca2+ releases that are present despite a reduction of sarcoplasmic reticulum content. Those releases increase forward mode Na+/Ca2+ exchanger type 1, thereby slowing repolarization and enabling L-type Ca2+ current reactivation. (Circ Res. 2014;115:919-928.)

Original languageEnglish
Pages (from-to)919-928
Number of pages10
JournalCirculation Research
Issue number11
StatePublished - 2014
Externally publishedYes


  • Arrhythmias
  • Calcium release
  • Cardiac
  • Long QT syndrome
  • Protein phosphatase
  • Ryanodine receptor


Dive into the research topics of 'Hyperphosphorylation of RyRs underlies triggered activity in transgenic rabbit model of LQT2 syndrome'. Together they form a unique fingerprint.

Cite this