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(Circulation. 2005;111:399-404.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Single-Channel Properties Support a Potential Contribution of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and I_f to Cardiac Arrhythmias

Guido Michels, MD; Fikret Er, MD; Ismail Khan, PhD; Michael Südkamp, MD; Stefan Herzig, MD; Uta C. Hoppe, MD

From the Department of Internal Medicine III (G.M., F.E., U.C.H.); Institute of Pharmacology (I.K., S.H.); Department of Cardiac Surgery (M.S.); and Center for Molecular Medicine (G.M., I.K., S.H., U.C.H.), University of Cologne, Cologne, Germany.

Correspondence to Uta C. Hoppe, MD, Department of Internal Medicine III, University of Cologne, Joseph-Stelzmann Strasse 9, 50924 Cologne, Germany. E-mail uta.hoppe{at}uni-koeln.de

Received July 5, 2004; revision received September 6, 2004; accepted October 6, 2004.

Background— The pacemaker current I_f is present in atrial and ventricular myocytes. However, it remains controversial whether I_f overexpression in diseased states might play a role for arrhythmogenesis, because first I_f activation in whole-cell recordings hardly overlapped the diastolic voltage of working myocardium.

Methods and Results— To obtain further insight into I_HCN and I_f properties, we provide for the first time detailed single-channel analysis of heterologously expressed hyperpolarization-activated cyclic nucleotide-gated (HCN) isoforms and native human I_f. HCN subtypes differed significantly in single-channel amplitude, conductance, and activation kinetics. Interestingly, threshold potentials of HCN isoforms were more positive than would have been expected from whole-cell measurements. Single-channel properties of cells cotransfected with HCN2 and HCN4 were distinct from cells expressing HCN2 or HCN4 alone, demonstrating that different HCN isoforms can influence current properties of a single HCN channel complex, thus providing direct functional evidence for HCN heteromerization. Pooled data of homomeric and heteromeric HCN channels and of native I_f extrapolated from maximum likelihood fits indicated a multistate gating scheme comprising 5 closed- and 4 open-channel states. Single-channel characteristics of I_f in human atrial myocytes closely resembled those of HCN4 or HCN2+HCN4, supporting the hypothesis that native I_f channels in atrial myocardium are heteromeric complexes composed of HCN4 and/or HCN2. Most interestingly, half-maximal activation of single-channel atrial I_f (–68.3±4.9 mV; k=–9.9±1.5; n=8) was well within the diastolic voltage range of human atrial myocardium.

Conclusions— These observations support a potential contribution of HCN/I_f to the arrhythmogenesis of working myocardium under pathological conditions.

Key Words: pacemakers • electrophysiology • ion channels • arrhythmia • myocytes

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