The G-protein-gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation.
The G-protein-gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation.
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DOI：
10.1085/jgp.201310996
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Mangoni ME
中科院分区：
文献类型：
--
作者：
Mesirca P;Marger L;Toyoda F;Rizzetto R;Audoubert M;Dubel S;Torrente AG;Difrancesco ML;Muller JC;Leoni AL;Couette B;Nargeot J;Clapham DE;Wickman K;Mangoni ME
窦房结 (SAN) 起搏器活动的副交感神经调节可调节多个离子通道以调节心率。 G 蛋白激活 K+ 电流 (IKACh) 在控制 SAN 起搏和心率中的功能作用尚不完全清楚。我们研究了 IKACh 缺失对 SAN 细胞起搏器活性的胆碱能调节以及模仿战斗或逃跑反应的生理情况下心率控制的功能影响。我们使用了 Girk4 (Kir3.4) 基因功能丧失的敲除小鼠（Girk4−/− 小鼠），该基因编码心脏 IKACh 通道的一个完整亚基。 Girk4−/− 小鼠的 SAN 起搏器细胞完全缺乏 IKACh。 IKACh 的缺失强烈降低了 SAN 细胞和分离的完整心脏起搏器活性的胆碱能调节。自由活动小鼠心电图的遥测记录显示，Girk4−/− 动物在 24 小时记录期内测得的心率适度增加 (10%)。尽管Girk4−/−小鼠心率调节的相对程度与野生型动物相似，但Girk4−/−动物在应激、体育锻炼或SAN起搏的药物β-肾上腺素刺激后静息心率的恢复明显延迟。我们得出的结论是，IKACh 在交感神经刺激后或直接 β-肾上腺素能刺激起搏器活动后心率恢复到静息水平的动力学中起着关键作用。因此，我们的研究揭示了 IKACh 在 SAN 生理学和心率调节中的新作用。
Parasympathetic regulation of sinoatrial node (SAN) pacemaker activity modulates multiple ion channels to temper heart rate. The functional role of the G-protein–activated K+ current (IKACh) in the control of SAN pacemaking and heart rate is not completely understood. We have investigated the functional consequences of loss of IKACh in cholinergic regulation of pacemaker activity of SAN cells and in heart rate control under physiological situations mimicking the fight or flight response. We used knockout mice with loss of function of the Girk4 (Kir3.4) gene (Girk4−/− mice), which codes for an integral subunit of the cardiac IKACh channel. SAN pacemaker cells from Girk4−/− mice completely lacked IKACh. Loss of IKACh strongly reduced cholinergic regulation of pacemaker activity of SAN cells and isolated intact hearts. Telemetric recordings of electrocardiograms of freely moving mice showed that heart rate measured over a 24-h recording period was moderately increased (10%) in Girk4−/− animals. Although the relative extent of heart rate regulation of Girk4−/− mice was similar to that of wild-type animals, recovery of resting heart rate after stress, physical exercise, or pharmacological β-adrenergic stimulation of SAN pacemaking was significantly delayed in Girk4−/− animals. We conclude that IKACh plays a critical role in the kinetics of heart rate recovery to resting levels after sympathetic stimulation or after direct β-adrenergic stimulation of pacemaker activity. Our study thus uncovers a novel role for IKACh in SAN physiology and heart rate regulation.
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影响因子：
11.4
作者：
Harzheim, Dagmar;Pfeiffer, K. Holger;Seifert, Reinhard
通讯作者：
Seifert, Reinhard
影响因子：
11.4
作者：
Herrmann, Stefan;Stieber, Juliane;Ludwig, Andreas
通讯作者：
Ludwig, Andreas
影响因子：
10.8
作者：
Mangoni, ME;Nargeot, J
通讯作者：
Nargeot, J
影响因子：
5.5
作者：
Marionneau, C;Couette, B;Demolombe, S
通讯作者：
Demolombe, S
DOI：
10.1073/pnas.081089398
发表时间：
2001-04-24
影响因子：
11.1
作者：
Ino, M;Yoshinaga, T;Mori, Y
通讯作者：
Mori, Y