Journal
CIRCULATION RESEARCH
Volume 89, Issue 1, Pages E8-E14Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hh1301.094395
Keywords
pacemaker current; gene expression; development; ventricle; HCN
Funding
- NHLBI NIH HHS [HL-28958] Funding Source: Medline
- NINDS NIH HHS [NS-36658] Funding Source: Medline
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Ventricular pacemaker current (I-f) shows distinct voltage dependence as a function of age, activating outside the physiological range in normal adult ventricle, but less negatively in neonatal ventricle. However, heterologously expressed HCN2 and HCN4, the putative molecular correlates of ventricular I-f, exhibit only a modest difference in activation voltage. We therefore prepared an adenoviral construct (AdHCN2) of HCN2, the dominant ventricular isoform at either age, and used it to infect neonatal and adult rat ventricular myocytes to investigate the role of maturation on current gating. The expressed current exhibited an 18-mV difference in activation (V-1/2-95.9 +/-1.9 in adult; -77.6 +/-1.6 mV in neonate), comparable to the 22-mV difference between native If in adult and neonatal cultures (V-1/2-98.7 versus -77.0 mV). This did not result from developmental differences in basal cAMP, because saturating cAMP in the pipette caused an equivalent positive shift in both preparations. In the neonate, AdHCN2 caused a significant increase in spontaneous rate compared with control (88 +/-5 versus 48 +/-4 bpm). In adult, where HCN2 activates more negatively, the effect was evident only during anodal excitation, requiring significantly less stimulus energy than control (2149 +/- 266 versus 3140 +/- 279 mV ms). Thus, ventricular maturational state influences the voltage dependence of expressed HCN2, resulting in distinct physiological impact of expressed channels in neonate and adult myocytes. The full text of this article is available at http://www.circresaha.org.
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