@article{8101211,
  abstract     = {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 (I-to) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I-to and that its overexpression might specifically alter PF I-to properties and repolarization. 
Objective: To assess the potential role of DPP6 in PF I-to. 
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 I-to differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I-to density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K+-channel interacting beta-subunit K+-channel interacting protein type-2, essential for normal expression of I-to 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 I-to; I-to 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 I-to 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 I-to composition) greatly enhanced I-to 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 I-to enhancement can greatly accelerate PF repolarization. 
Conclusions: These results point to a previously unknown central role of DPP6 in PF I-to, 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.},
  author       = {Xiao, Ling and Koopmann, Tamara T and Ordog, Balazs and Postema, Pieter G and Verkerk, Arie O and Iyer, Vivek and Sampson, Kevin J and Boink, Gerard JJ and Mamarbachi, Maya A and Varro, Andras and Jordaens, Luc and Res, Jan and Kass, Robert S and Wilde, Arthur A and Bezzina, CR and Nattel, Stanley},
  issn         = {0009-7330},
  journal      = {CIRCULATION RESEARCH},
  keywords     = {ECG,cardiac arrhythmia mechanisms,genetic arrhythmia syndromes,molecular electrophysiology,potassium channels,sudden death,ventricular tachycardia arrhythmia,LONG QT SYNDROME,CONGESTIVE-HEART-FAILURE,BRUGADA-SYNDROME,K+-CURRENTS,IONIC MECHANISMS,GENE KNOCKDOWN,CURRENT I,EXPRESSION,CANINE,CELLS},
  language     = {eng},
  number       = {10},
  pages        = {1310--1322},
  title        = {Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation},
  url          = {http://dx.doi.org/10.1161/CIRCRESAHA.112.300227},
  volume       = {112},
  year         = {2013},
}

Altmetric

View in Altmetric

Web of Science

Times cited: