Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2
Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2
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DOI：
10.1093/emboj/cdg032
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发表时间：
2003-01-15
期刊：
影响因子：
11.4
通讯作者：
Hofmann, F
中科院分区：
文献类型：
--
作者：
Ludwig, A;Budde, T;Hofmann, F
超极化激活阳离子（HCN）通道被认为参与心脏起搏器去极化的产生以及神经元兴奋性和可塑性的控制。四个单独的HCN通道亚型（HCN 1 -4）对这些不同功能的贡献尚不清楚。在这里，我们表明，HCN 2缺陷小鼠表现出自发性失神发作。这些小鼠的丘脑皮质中继神经元显示HCN电流几乎完全丧失，导致静息膜电位的显著超极化转变，对去极化输入的反应改变和对振荡的敏感性增加。HCN 2基因敲除小鼠还表现出心脏窦性心律失常，窦房HCN电流减少，最大舒张电位向超极化值偏移。心肌细胞特异性缺失HCN 2的小鼠表现出与缺乏HCN 2的小鼠相同的心律失常，表明心律失常确实是由窦房功能障碍引起的。我们的研究结果定义的HCN 2亚基的生理作用作为一个主要的决定因素的膜静息电位，需要定期的心脏和神经元的节奏。
Hyperpolarization-activated cation (HCN) channels are believed to be involved in the generation of cardiac pacemaker depolarizations as well as in the control of neuronal excitability and plasticity. The contributions of the four individual HCN channel isoforms (HCN1-4) to these diverse functions are not known. Here we show that HCN2-deficient mice exhibit spontaneous absence seizures. The thalamocortical relay neurons of these mice displayed a near complete loss of the HCN current, resulting in a pronounced hyperpolarizing shift of the resting membrane potential, an altered response to depolarizing inputs and an increased susceptibility for oscillations. HCN2-null mice also displayed cardiac sinus dysrhythmia, a reduction of the sinoatrial HCN current and a shift of the maximum diastolic potential to hyperpolarized values. Mice with cardiomyocyte-specific deletion of HCN2 displayed the same dysrhythmia as mice lacking HCN2 globally, indicating that the dysrhythmia is indeed caused by sinoatrial dysfunction. Our results define the physiological role of the HCN2 subunit as a major determinant of membrane resting potential that is required for regular cardiac and neuronal rhythmicity.