Functional comparison of HCN isoforms expressed in ventricular and HEK 293 cells.
Pacemaker current (I(f)) encoded by the HCN gene family contributes importantly to cardiac rhythm. That contribution depends on the biophysical characteristics of I(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 approximately equal 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.
Department of Pharmacology and Center for Molecular Therapeutics, Columbia University, 630W 168th St., New York, NY 10032, USA.
Jihong
J
Qu
Claudia
C
Altomare
Annalisa
A
Bucchi
Dario
D
DiFrancesco
Richard B
RB
Robinson
D000818:Animals; D002478:Cells, Cultured; D054815:Cyclic Nucleotide-Gated Cation Channels; D015870:Gene Expression / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology*; D015221:Potassium Channels
D054815:Cyclic Nucleotide-Gated Cation Channels; C578710:HCN2 protein, human; C119587:HCN4 protein, human; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels