title: Expression and function of a biological pacemaker in canine heart.
abstract: BACKGROUND
  We hypothesized that localized overexpression of the hyperpolarization-activated, cyclic nucleotide-gated (HCN2) pacemaker current isoform in canine left atrium (LA) would constitute a novel biological pacemaker.
  
  
  RESULTS
  Adenoviral constructs of mouse HCN2 and green fluorescent protein (GFP) or GFP alone were injected into LA, terminal studies performed 3 to 4 days later, hearts removed, and myocytes examined for native and expressed pacemaker current (I(f)). Spontaneous LA rhythms occurred after vagal stimulation-induced sinus arrest in 4 of 4 HCN2+GFP dogs and 0 of 3 GFP dogs (P<0.05). Native I(f) in nonexpressed atrial myocytes was 7+/-4 pA at -130 mV (n=5), whereas HCN2+GFP LA had expressed pacemaker current (I(HCN2)) of 3823+/-713 pA at -125 mV (n=10) and 768+/-365 pA at -85 mV.
  
  
  CONCLUSIONS
  HCN2 overexpression provides an I(f)-based pacemaker sufficient to drive the heart when injected into a localized region of atrium, offering a promising gene therapy for pacemaker disease.
authors.affiliation: Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Jihong
authors.initials: J
authors.lastname: Qu
authors.forename: Alexei N
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: Peter
authors.initials: P
authors.lastname: Danilo
authors.forename: Iryna
authors.initials: I
authors.lastname: Shlapakova
authors.forename: Ira S
authors.initials: IS
authors.lastname: Cohen
authors.forename: Richard B
authors.initials: RB
authors.lastname: Robinson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rosen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016275:Atrial Function; D001683:Biological Clocks; D002478:Cells, Cultured; D004285:Dogs; D004553:Electric Conductivity; D004562:Electrocardiography; D005260:Female; D005822:Genetic Vectors; D006325:Heart Atria / Q000378:metabolism*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015221:Potassium Channels
chemical_list: C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels