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

(2013) CIRCULATION RESEARCH. 112(10). p.1310-1322
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Organization
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.
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

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MLA
Xiao, Ling et al. “Unique Cardiac Purkinje Fiber Transient Outward Current Β-subunit Composition: a Potential Molecular Link to Idiopathic Ventricular Fibrillation.” CIRCULATION RESEARCH 112.10 (2013): 1310–1322. Print.
APA
Xiao, L., Koopmann, T. T., Ordog, B., Postema, P. G., Verkerk, A. O., Iyer, V., Sampson, K. J., et al. (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.
Chicago author-date
Xiao, Ling, Tamara T Koopmann, Balazs Ordog, Pieter G Postema, Arie O Verkerk, Vivek Iyer, Kevin J Sampson, et al. 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.
Chicago author-date (all authors)
Xiao, Ling, Tamara T Koopmann, Balazs Ordog, Pieter G Postema, Arie O Verkerk, Vivek Iyer, Kevin J Sampson, Gerard JJ Boink, Maya A Mamarbachi, Andras Varro, Luc Jordaens, Jan Res, Robert S Kass, Arthur A Wilde, CR Bezzina, and Stanley Nattel. 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.
Vancouver
1.
Xiao L, Koopmann TT, Ordog B, Postema PG, Verkerk AO, Iyer V, et al. Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation. CIRCULATION RESEARCH. 2013;112(10):1310–22.
IEEE
[1]
L. Xiao et al., “Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation,” CIRCULATION RESEARCH, vol. 112, no. 10, pp. 1310–1322, 2013.
@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},
}

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