Calcium influx through If channels in rat ventricular myocytes.
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.
Yu
Xiao
X
Institute of Molecular Medicine, Peking University, Beijing 100871, China.
Chen
Xiao-Wei
XW
Zhou
Peng
P
Yao
Lijun
L
Liu
Tao
T
Zhang
Bo
B
Li
Ying
Y
Zheng
Hui
H
Zheng
Liang-Hong
LH
Zhang
Claire Xi
CX
Bruce
Iain
I
Ge
Jun-Bo
JB
Wang
Shi-Qiang
SQ
Hu
Zhi-An
ZA
Yu
Han-Gang
HG
Zhou
Zhuan
Z
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
C513836:HCN4 protein, rat; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D002118:Calcium