Calcium influx through If channels in rat ventricular myocytes

• Published in: American Journal of Physiology: Cell Physiology 2007-03, Vol.292 (3), p.C1147-C1155
• Main Authors: Yu, Xiao, Chen, Xiao-Wei, Zhou, Peng, Yao, Lijun, Liu, Tao, Zhang, Bo, Li, Ying, Zheng, Hui, Zheng, Liang-Hong, Zhang, Claire Xi, Bruce, Iain, Ge, Jun-Bo, Wang, Shi-Qiang, Hu, Zhi-An, Yu, Han-Gang, Zhou, Zhuan
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium Signaling - physiology; Cells, Cultured; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ion Channel Gating - physiology; Ion Channels - metabolism; Myocytes, Cardiac - physiology; Potassium Channels - metabolism; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Ventricular Function
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00598.2005

1 Institute of Molecular Medicine and State Key Laboratory of Biomembrane Engineering, Peking University, Beijing, 2 Department of Physiology, Third Military Medical University, Chongqing, 3 College of Life Sciences, Peking University, Beijing, 4 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital of Fudan University, Shanghai, and 5 Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China; and 6 Departments 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 ( I f )/neuronal ( I h ) 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 I h channels in neurons. This raises the possibility of Ca 2+ permeation in I f , the I h counterpart in cardiac myocytes, because of their structural homology. We performed simultaneous measurement of fura-2 Ca 2+ signals and whole cell currents produced by HCN2 and HCN4 channels (the 2 cardiac isoforms present in ventricles) expressed in HEK293 cells and by I f in rat ventricular myocytes. We observed Ca 2+ influx when HCN/ I f channels were activated. Ca 2+ influx was increased with stronger hyperpolarization or longer pulse duration. Cesium, an I f channel blocker, inhibited I f and Ca 2+ influx at the same time. Quantitative analysis revealed that Ca 2+ flux contributed to 0.5% of current produced by the HCN2 channel or I f . The associated increase in Ca 2+ influx was also observed in spontaneously hypertensive rat (SHR) myocytes in which I f current density is higher than that of normotensive rat ventricle. In the absence of EGTA (a Ca 2+ chelator), preactivation of I f channels significantly reduced the action potential duration, and the effect was blocked by another selective I f channel blocker, ZD-7288. In the presence of EGTA, however, preactivation of I f channels had no effects on action potential duration. Our data extend our previous discovery of Ca 2+ influx in I h channels in neurons to I f 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 Medici