Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels
Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels
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DOI：
10.1113/jphysiol.2006.110437
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发表时间：
2006-09-01
影响因子：
5.5
通讯作者：
Larsson, H. Peter
中科院分区：
文献类型：
--
作者：
Elinder, Fredrik;Mannikko, Roope;Larsson, H. Peter
超极化激活的环核苷酸门控（HCN）通道调节心脏和大脑中的起搏器活动。以前，我们表明，spHCN和HCN 1通道在其电压依赖性中经历模式转换，当从超极化电位与去极化电位相比测量时，电导与电压曲线的位移超过+50 mV。此外，离子电流的动力学与这些电压偏移平行变化。在这里报道的研究中，我们测试了较慢的心脏HCN通道是否也显示类似的模式转换。我们发现，HCN 2和HCN 4通道表达的卵母细胞从青蛙非洲爪蟾不显示激活动力学的变化，我们观察到的sphHCN和HCN 1。然而，HCN 2和HCN 4通道显示其尾电流的变化，这表明这些通道也经历模式转换，模式转换的基础上的构象变化是由于HCN通道的保守方面。与计算机建模，我们表明，在相对缓慢的开放动力学和快速的模式转换转换的通道，如HCN 2和HCN 4通道，模式转换的影响是不容易观察到的，除了在尾部动力学。窦房结动作电位的计算机模拟表明，HCN 2通道，与HCN 1通道一起，是心脏放电频率的重要调节器，并且模式转换是防止心房放电的重要特性。我们的结论是，虽然所有的HCN通道似乎经历模式转换-因此可以用来防止放电发射-它主要是观察到的离子电流从HCN通道具有更快的动力学。
Hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channels regulate pacemaker activity in the heart and the brain. Previously, we showed that spHCN and HCN1 channels undergo mode shifts in their voltage dependences, shifting the conductance versus voltage curves by more than +50 mV when measured from a hyperpolarized potential compared to a depolarized potential. In addition, the kinetics of the ionic currents changed in parallel to these voltage shifts. In the studies reported here, we tested whether slower cardiac HCN channels also display similar mode shifts. We found that HCN2 and HCN4 channels expressed in oocytes from the frog Xenopus laevis do not display the activation kinetic changes that we observed in spHCN and HCN1. However, HCN2 and HCN4 channels display changes in their tail currents, suggesting that these channels also undergo mode shifts and that the conformational changes underlying the mode shifts are due to conserved aspects of HCN channels. With computer modelling, we show that in channels with relatively slow opening kinetics and fast mode-shift transitions, such as HCN2 and HCN4 channels, the mode shift effects are not readily observable, except in the tail kinetics. Computer simulations of sino-atrial node action potentials suggest that the HCN2 channel, together with the HCN1 channel, are important regulators of the heart firing frequency and that the mode shift is an important property to prevent arrhythmic firing. We conclude that although all HCN channels appear to undergo mode shifts - and thus may serve to prevent arrhythmic firing - it is mainly observable in ionic currents from HCN channels with faster kinetics.