Key result
Activation of HCN/If channels in rat ventricular myocytes and HEK293 cells resulted in Ca2+ influx, which contributed to approximately 0.5% of the current produced by the HCN2 channel or If.
This study demonstrates that calcium ions can permeate through If (HCN) channels in cardiac myocytes, extending previous findings in neurons and showing an effect on action potential duration.
No immediate clinical implications; extends neuronal Ca2+ permeation data to cardiac myocytes and leaves open human relevance.
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.
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Yu et al. (2006) studied this question. Activation of HCN/If channels vs. Channel blockers (Cesium, ZD-7288) was evaluated on Ca2+ influx and current contribution. Activation of HCN/If channels in rat ventricular myocytes and HEK293 cells resulted in Ca2+ influx, which contributed to approximately 0.5% of the current produced by the HCN2 channel or If.
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