title: Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation.
abstract: BACKGROUND
  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).
  
  
  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 β-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.
authors.affiliation: Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada.
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.forename: Balázs
authors.initials: B
authors.lastname: Ördög
authors.forename: Pieter G
authors.initials: PG
authors.lastname: Postema
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.forename: Vivek
authors.initials: V
authors.lastname: Iyer
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Sampson
authors.forename: Gerard J J
authors.initials: GJ
authors.lastname: Boink
authors.forename: Maya A
authors.initials: MA
authors.lastname: Mamarbachi
authors.forename: Andras
authors.initials: A
authors.lastname: Varro
authors.forename: Luc
authors.initials: L
authors.lastname: Jordaens
authors.forename: Jan
authors.initials: J
authors.lastname: Res
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Wilde
authors.forename: C R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D055785:Gene Knockdown Techniques; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D051605:Kv Channel-Interacting Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011690:Purkinje Fibers / Q000473:pathology / Q000502:physiology*; D051672:Shal Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019789:Tetraethylammonium / Q000494:pharmacology; D014162:Transfection; D014693:Ventricular Fibrillation / Q000503:physiopathology*
chemical_list: D051605:Kv Channel-Interacting Proteins; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D051672:Shal Potassium Channels; D019789:Tetraethylammonium; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
keywords: ECG; cardiac arrhythmia mechanisms; genetic arrhythmia syndromes; molecular electrophysiology; potassium channels; sudden death; ventricular tachycardia arrhythmia