Unique cardiac Purkinje fiber transient outward current β-subunit composition: A potential molecular link to idiopathic ventricular fibrillation

Ling Xiao, Tamara T. Koopmann, Balázs Ördög, Pieter G. Postema, Arie O. Verkerk, Vivek Iyer, Kevin J. Sampson, Gerard J.J. Boink, Maya A. Mamarbachi, Andras Varro, Luc Jordaens, Jan Res, Robert S. Kass, Arthur A. Wilde, C. R. Bezzina, Stanley Nattel

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Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current (Ito) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF Ito and that its overexpression might specifically alter PF Ito properties and repolarization. Objective: To assess the potential role of DPP6 in PF Ito. Methods and Results: Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and ventricular muscle I to had similar density, but PF Ito differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Ito density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K+-channel interacting β-subunit K+-channel interacting protein type-2, essential for normal expression of Ito in ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small Ito; Ito amplitude was greatly enhanced by coexpression with K+-channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K+-channel interacting protein type-2 failed to alter Ito compared with Kv4.3/K+-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF Ito composition) greatly enhanced Ito compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that Ito enhancement can greatly accelerate PF repolarization. Conclusions: These results point to a previously unknown central role of DPP6 in PF Ito, with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation.

Original languageEnglish
Pages (from-to)1310-1322
Number of pages13
JournalCirculation research
Issue number10
Publication statusPublished - Apr 1 2013



  • Cardiac arrhythmia mechanisms
  • ECG
  • Genetic arrhythmia syndromes
  • Molecular electrophysiology
  • Potassium channels
  • Sudden death
  • Ventricular tachycardia arrhythmia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Xiao, L., Koopmann, T. T., Ördög, B., Postema, P. G., Verkerk, A. O., Iyer, V., Sampson, K. J., Boink, G. J. J., Mamarbachi, M. A., Varro, A., Jordaens, L., Res, J., Kass, R. S., Wilde, A. A., Bezzina, C. R., & Nattel, S. (2013). Unique cardiac Purkinje fiber transient outward current β-subunit composition: A potential molecular link to idiopathic ventricular fibrillation. Circulation research, 112(10), 1310-1322. https://doi.org/10.1161/CIRCRESAHA.112.300227