HCN2 overexpression in newborn and adult ventricular myocytes - Distinct effects on gating and excitability

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, heterologou sly expressed HCN2 and HCN4, the putative molecular correlates of ventricul ar I-f, exhibit only a modest difference in activation voltage. We therefor e prepared an adenoviral construct (AdHCN2) of HCN2, the dominant ventricul ar isoform at either age, and used it to infect neonatal and adult rat vent ricular myocytes to investigate the role of maturation on current gating. T he 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 dif ference 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 cAM P, because saturating cAMP in the pipette caused an equivalent positive shi ft in both preparations. In the neonate, AdHCN2 caused a significant increa se 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 tha n control (2149 +/- 266 versus 3140 +/- 279 mV ms). Thus, ventricular matur ational state influences the voltage dependence of expressed HCN2, resultin g in distinct physiological impact of expressed channels in neonate and adu lt myocytes. The full text of this article is available at http://www.circr esaha.org.