title: Calcium influx through If channels in rat ventricular myocytes.
abstract: 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 approximately 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.
authors.affiliation: Institute of Molecular Medicine, Peking University, Beijing 100871, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.forename: Lijun
authors.initials: L
authors.lastname: Yao
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Liang-Hong
authors.initials: LH
authors.lastname: Zheng
authors.forename: Claire Xi
authors.initials: CX
authors.lastname: Zhang
authors.forename: Iain
authors.initials: I
authors.lastname: Bruce
authors.forename: Jun-Bo
authors.initials: JB
authors.lastname: Ge
authors.forename: Shi-Qiang
authors.initials: SQ
authors.lastname: Wang
authors.forename: Zhi-An
authors.initials: ZA
authors.lastname: Hu
authors.forename: Han-Gang
authors.initials: HG
authors.lastname: Yu
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000502:physiology*; D007473:Ion Channels / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology*; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016276:Ventricular Function
chemical_list: C513836:HCN4 protein, rat; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D002118:Calcium