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Am J Physiol Cell Physiol 292: C1147-C1155, 2007. First published October 25, 2006; doi:10.1152/ajpcell.00598.2005 Free Article
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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Calcium influx through If channels in rat ventricular myocytes

Xiao Yu,1,* Xiao-Wei Chen,1,2,* Peng Zhou,3 Lijun Yao,1 Tao Liu,1 Bo Zhang,1 Ying Li,4 Hui Zheng,1 Liang-Hong Zheng,1 Claire Xi Zhang,1 Iain Bruce,5 Jun-Bo Ge,4 Shi-Qiang Wang,3 Zhi-An Hu,2 Han-Gang Yu,6 and Zhuan Zhou1

1Institute of Molecular Medicine and State Key Laboratory of Biomembrane Engineering, Peking University, Beijing, 2Department of Physiology, Third Military Medical University, Chongqing, 3College of Life Sciences, Peking University, Beijing, 4Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital of Fudan University, Shanghai, and 5Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China; and 6Departments of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia

Submitted 1 December 2005 ; accepted in final form 9 October 2006

The hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, or cardiac (If)/neuronal (Ih) time- and voltage-dependent inward cation current channels, are conventionally considered as monovalent-selective channels. Recently we discovered that calcium ions can permeate through HCN4 and Ih channels in neurons. This raises the possibility of Ca2+ permeation in If, the Ih counterpart in cardiac myocytes, because of their structural homology. We performed simultaneous measurement of fura-2 Ca2+ signals and whole cell currents produced by HCN2 and HCN4 channels (the 2 cardiac isoforms present in ventricles) expressed in HEK293 cells and by If in rat ventricular myocytes. We observed Ca2+ influx when HCN/If channels were activated. Ca2+ influx was increased with stronger hyperpolarization or longer pulse duration. Cesium, an If channel blocker, inhibited If and Ca2+ influx at the same time. Quantitative analysis revealed that Ca2+ flux contributed to ~0.5% of current produced by the HCN2 channel or If. The associated increase in Ca2+ influx was also observed in spontaneously hypertensive rat (SHR) myocytes in which If current density is higher than that of normotensive rat ventricle. In the absence of EGTA (a Ca2+ chelator), preactivation of If channels significantly reduced the action potential duration, and the effect was blocked by another selective If channel blocker, ZD-7288. In the presence of EGTA, however, preactivation of If channels had no effects on action potential duration. Our data extend our previous discovery of Ca2+ influx in Ih channels in neurons to If channels in cardiac myocytes.

calcium ion flux; hyperpolarization-activated, cyclic nucleotide-gated/cardiac time- and volume-dependent cation current channels


Address for reprint requests and other correspondence: Z. Zhou or H.-G. Yu, Institute of Molecular Medicine, Peking Univ., Beijing 100871, China (e-mail: zzhou{at}pku.edu.cn or hyu{at}hsc.wvu.edu)




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