Mechanistic role of If revealed by induction of ventricular automaticity by somatic gene transfer of gating-engineered pacemaker (HCN) channels

Tian Xue, Chung Wah Siu, Deborah K. Lieu, Chu Pak Lau, Hung Fat Tse, Ronald A. Li

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND - Although If, encoded by the hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channel gene family, is known to be functionally important in pacing, its mechanistic action is largely inferential and indeed somewhat controversial. To dissect in detail the role of If, we investigated the functional consequences of overexpressing in adult guinea pig left ventricular cardiomyocytes (LVCMs) various HCN1 constructs that have been engineered to exhibit different gating properties. METHODS AND RESULTS - We created the recombinant adenoviruses Ad-CMV-GFP-IRES (CGI), Ad-CGI-HCN1, Ad-CGI-HCN1-ΔΔΔ, and Ad-CGI-HCN1-Ins, which mediate ectopic expression of GFP alone, WT, EVY235-7ΔΔΔ, and Ins HCN1 channels, respectively; EVY235-7ΔΔΔ and Ins encode channels in which the S3-S4 linkers have been shortened and lengthened to favor and inhibit opening, respectively. Ad-CGI-HCN1, Ad-CGI-HCN1-ΔΔΔ, and Ad-CGI-HCN1-Ins, but not control Ad-CGI, transduction of LVCMs led to robust expression of If with comparable densities when fully open (≈-22 pA/pF at -140 mV; P>0.05) but distinctive activation profiles (V1/2=-70.8±0.6, -60.4±0.7, and -87.7±0.7 mV; P

Original languageEnglish (US)
Pages (from-to)1839-1850
Number of pages12
JournalCirculation
Volume115
Issue number14
DOIs
StatePublished - Apr 2007
Externally publishedYes

Keywords

  • Genes
  • Ion channels
  • Pacemakers
  • Sinoatrial node
  • Tissue engineering

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Mechanistic role of If revealed by induction of ventricular automaticity by somatic gene transfer of gating-engineered pacemaker (HCN) channels'. Together they form a unique fingerprint.

Cite this