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1 Peking University, Institute of Molecular Medicine, Beijing, Beijing, China; Shanghai Institutes for Biological Sciences, CAS, Institute of Neuroscience, Shanghai, China
2 Peking University, Institute of Molecular Medicine, Beijing, China
3 Peking University, College of Life Sciences, Beijing, China
4 Peking University, Institute of Molecular Medicine, Beijing, Beijing, China; Zhejiang University School of Medicine, Department of Neurobiology, Hangzhou, Zhejiang, China
5 Peking University, Institute of Molecular Medicine, Beijing, Beijing, China; Zhongshan Hospital of Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China
6 The University of Hong Kong, Department of Physiology, Hong Kong, Hong Kong, China
7 Peking University, College of Life Sciences, Beijing, Beijing, China
8 Third Military Medical University, Department of Physiology, congqing, China
9 SUNY, Departments of Physiology and Biophysics, Stony Brook, New York, United States
* To whom correspondence should be addressed. E-mail: zzhou{at}pku.edu.cn.
The Hyperpolarization-activated, Cyclic Nucleotide-gated (HCN) channels, or If/Ih channels, are conventionally considered as monovalent-selective channels. Recently, we discovered that Ca2+ ions can permeate HCN4 and Ih channels. This discovery raises the possibility of Ca2+ permeation in cardiac pacemaker channels due to the channel structural homology. We simultaneously measured the fura-2 Ca2+ signals and whole-cell currents induced by HCN2 and HCN4 channels expressed in HEK293 cells and by If in rat ventricular myocytes. We observed Ca2+ influx in open, but not in close, HCN/If channels. Ca2+ influx was increased with stronger hyperpolarization or longer pulse duration. Cesium (2 mM), an If channel blocker, inhibited If and Ca2+ influx at the same time. Quantitative analysis revealed Ca2+ flux contributed to about 0.5% of IHCN2 or If. The associated increase in Ca influx was also observed in spontaneously hypertensive rat (SHR) myocytes in which If current density is higher than that in normotensive rat ventricle. Pre-activation of If chcannels significantly reduced the action potential duration. Our data demonstrate for the first time that Ca2+ can permeate If channels and Ca2+ influx through open If channels at negative potentials may modulate action potential duration.
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