Pacemaker current (I_f) encoded by the HCN gene family contributes importantly to cardiac rhythm. That contribution depends on the biophysical characteristics ofI_f, such as voltage dependence, which vary markedly with cardiac region, development and disease. Heterologous expression studies of individual HCN isoforms have failed to account for the diverse functionality of the native current. To investigate the influence of cellular environment on the gating of HCN channels, we compared the functional characteristics of HCN2 and HCN4, the two major ventricular isoforms, when over-expressed in a normal context (neonatal myocytes) and in a heterologous context (HEK 293 cells). Independent of cell type, HCN4 activates substantially slower than HCN2 and with a half-maximum activation voltage ≅10 mV less negative. However, both isoforms activate more positively in myocytes than in HEK 293 cells. The latter result suggests a context dependence (i.e. cell-type specificity) to HCN voltage dependence that exerts a comparable influence on these two isoforms. This is distinct from the inherent difference in the biophysical properties of HCN2 and HCN4.

Authors and Affiliations

1. Department of Pharmacology and Center for Molecular Therapeutics, Columbia University, 630W 168th St., New York, NY 10032, USA, , , , ,

   Jihong Qu & Richard B. Robinson

2. Department of General Physiology and Biochemistry, Molecular Physiology and Neurophysiology and INFM- Milano Un. Unit, via Celoria 26, 20133 Milan, Italy, , , , ,

   Claudia Altomare, Annalisa Bucchi & Dario DiFrancesco

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