Complete atrial-specific knockout of sodium-calcium exchange eliminates sinoatrial node pacemaker activity.
Complete atrial-specific knockout of sodium-calcium exchange eliminates sinoatrial node pacemaker activity.
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DOI：
10.1371/journal.pone.0081633
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Goldhaber JI
中科院分区：
文献类型：
--
作者：
Groenke S;Larson ED;Alber S;Zhang R;Lamp ST;Ren X;Nakano H;Jordan MC;Karagueuzian HS;Roos KP;Nakano A;Proenza C;Philipson KD;Goldhaber JI
心脏中窦房结起搏活动的起源一直存在争议。领先的候选方案是通过HCN4通道的“有趣”电流(IF)的舒张期去极化(“膜钟”假说)，响应细胞内钙循环的心肌钠钙交换去极化(NCX1)(“钙钟”假说)，以及两者的组合(“耦合时钟”)。为了解决这一争议，我们使用Cre/loxP技术培育了心房特异的NCX1 KO小鼠。NCX1蛋白在包括窦房结在内的KO心房组织中未检测到。体表心电图和心内电图显示KO患者无心房除极和慢交界性逃逸节律，对β肾上腺素能和毒鼠强刺激有适当的反应。虽然KO心房处于静止状态，但可被外部起搏刺激，这表明细胞之间的电耦合保持完好。尽管在膜片钳分离的KO SAN细胞中IF的电生理特性正常，但起搏器活动缺失。在所有KO窦房结细胞中均存在反复出现的钙火花，表明钙循环持续存在，但与肌膜解偶联。我们得出结论，NCX1是小鼠窦房结正常起搏活动所必需的。
The origin of sinoatrial node (SAN) pacemaker activity in the heart is controversial. The leading candidates are diastolic depolarization by “funny” current (If) through HCN4 channels (the “Membrane Clock“ hypothesis), depolarization by cardiac Na-Ca exchange (NCX1) in response to intracellular Ca cycling (the "Calcium Clock" hypothesis), and a combination of the two (“Coupled Clock”). To address this controversy, we used Cre/loxP technology to generate atrial-specific NCX1 KO mice. NCX1 protein was undetectable in KO atrial tissue, including the SAN. Surface ECG and intracardiac electrograms showed no atrial depolarization and a slow junctional escape rhythm in KO that responded appropriately to β-adrenergic and muscarinic stimulation. Although KO atria were quiescent they could be stimulated by external pacing suggesting that electrical coupling between cells remained intact. Despite normal electrophysiological properties of If in isolated patch clamped KO SAN cells, pacemaker activity was absent. Recurring Ca sparks were present in all KO SAN cells, suggesting that Ca cycling persists but is uncoupled from the sarcolemma. We conclude that NCX1 is required for normal pacemaker activity in murine SAN.
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影响因子：
6.1
作者：
Gizurarson, S.;Lorentzon, M.;Omerovic, E.
通讯作者：
Omerovic, E.
影响因子：
20.1
作者：
Gao Z;Rasmussen TP;Li Y;Kutschke W;Koval OM;Wu Y;Wu Y;Hall DD;Joiner ML;Wu XQ;Swaminathan PD;Purohit A;Zimmerman K;Weiss RM;Philipson KD;Song LS;Hund TJ;Anderson ME
通讯作者：
Anderson ME
影响因子：
5.5
作者：
Hüser, J;Blatter, LA;Lipsius, SL
通讯作者：
Lipsius, SL
影响因子：
10.8
作者：
Mangoni, ME;Nargeot, J
通讯作者：
Nargeot, J
影响因子：
6
作者：
Jordan, Maria C.;Henderson, Scott A.;Han, Tieyan;Fishbein, Michael C.;Philipson, Kenneth D.;Roos, Kenneth P.
通讯作者：
Roos, Kenneth P.