Unique cardiac Purkinje fiber transient outward current β-subunit composition: A potential molecular link to idiopathic ventricular fibrillation
Circulation Research , Volume 112 - Issue 10 p. 1310- 1322
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 Itoand that its overexpression might specifically alter PF Itoproperties 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 Itohad similar density, but PF Itodiffered from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, Itodensity 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 Itoin 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; Itoamplitude 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 Itocompared with Kv4.3/K+-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF Itocomposition) greatly enhanced Itocompared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that Itoenhancement 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.
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|Organisation||Erasmus MC: University Medical Center Rotterdam|
Xiao, L, Koopmann, T.T, Ördög, B, Postema, P.G, Verkerk, A.O, Iyer, V, … 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. doi:10.1161/CIRCRESAHA.112.300227