Defective ''pacemaker'' current (I-h) in a zebrafish mutant with a slow heart rate
Defective ''pacemaker'' current (I-h) in a zebrafish mutant with a slow heart rate
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DOI：
10.1073/pnas.94.9.4554
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发表时间：
1997-04-29
影响因子：
11.1
通讯作者：
Fishman, MC
中科院分区：
文献类型：
--
作者：
Baker, K;Warren, KS;Fishman, MC
在细胞水平上，心脏起搏（其设定心跳的速率和节律）是由动作电位之间发生的缓慢膜去极化产生的。几种离子电流可以解释这种起搏电位，但它们的相对突出性是有争议的，并且不知道哪些离子电流实际上在体内发挥起搏作用。为了将单个心脏细胞中的电流与int-act心脏的节律特性相关联，我们研究了慢mo（smo），这是我们在斑马鱼Danio I el io中发现的隐性突变。这种突变导致胚胎心率降低，这是我们可以量化的特性，因为胚胎是透明的，我们开发了从斑马鱼胚胎培养心脏细胞的方法，发现即使在培养中，来自smo的细胞也继续相对缓慢地跳动，通过膜片钳分析，我们发现在其他物种中注意到的大量心脏电流存在于这些培养的细胞中，包括钠，T型和L型钙电流和几种钾电流，所有这些在突变体中都是正常的，唯一的异常似乎是具有I-h特性的超极化激活内向电流，这是以前在神经系统、起搏器和其他心脏组织中描述的电流，Smo心肌细胞具有I-h的减少，这似乎是由于I-h电流的一个动力学分量的严重减少。这提供了强有力的证据表明，I-h是完整心脏起搏行为的重要贡献者。
At a cellular level, cardiac pacemaking, which sets the rate and rhythm of the heartbeat, is produced by the slow membrane depolarization that occurs between action potentials, Several ionic currents could account for this pacemaker potential, but their relative pi-eminence is controversial, and it is not known which ones actually play a pacemaking role ire vivo. To correlate currents in individual heart cells with the rhythmic properties of the int-act heart, we have examined slow mo (smo), a recessive mutation we discovered in the zebrafish Danio I el io. This mutation causes a reduced heart rate in the embryo, a property we can quantitate because the embryo is transparent, We developed methods for culture of cardiocytes from zebrafish embryos and found that, even in culture, cells from smo continue to beat relatively slowly, By patch-clamp analysis, we discovered that a large repertoire of cardiac currents noted in other species are present in these cultured cells, including sodium, T-type, and L-type calcium and several potassium currents, all of which appear normal in the mutant, The only abnormality appears to be in a hyperpolarization-activated inward current with the properties of I-h, a current described previously in the nervous system, pacemaker, and other cardiac tissue, smo cardiomyocytes have a reduction in I-h that appears to result from severe diminution of one kinetic component of the I-h current. This provides strong evidence that I-h is an important contributor to the pacemaking behavior of the intact heart.