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(Circulation Research. 2001;89:e8.)
© 2001 American Heart Association, Inc.

UltraRapid Communication

HCN2 Overexpression in Newborn and Adult Ventricular Myocytes

Distinct Effects on Gating and Excitability

Jihong Qu, Andrea Barbuti, Lev Protas, Bina Santoro, Ira S. Cohen, Richard B. Robinson

From the Department of Pharmacology (J.Q., A.B., L.P., R.B.R.), Center for Molecular Therapeutics (I.S.C., R.B.R.) and Center for Neurobiology and Behavior (B.S.), Columbia University, New York, and Department of Physiology and Biophysics and Institute of Molecular Cardiology (I.S.C.), State University of New York, Stony Brook.

Correspondence to Richard B. Robinson, PhD, Department of Pharmacology, Columbia University, 630 W 168th St, New York, NY 10032. E-mail rbr1{at}columbia.edu

Abstract

Abstract—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 I_f 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.

Key Words: pacemaker current • gene expression • development • ventricle • HCN

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