Can PKA activators rescue Na+ channel function in epicardial border zone cells that survive in the infarcted canine heart?
Can PKA activators rescue Na+ channel function in epicardial border zone cells that survive in the infarcted canine heart?
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DOI：
10.1016/j.cardiores.2004.06.021
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发表时间：
2004-11-01
影响因子：
10.8
通讯作者：
Boyden, PA
中科院分区：
文献类型：
--
作者：
Baba, S;Dun, W;Boyden, PA
目的和方法：在本研究中，我们观察了一种PKA刺激的鸡尾酒对正常心外膜细胞(NZs)和5天梗死犬心脏(IZS)心外膜区散在细胞钠电流的影响。结果：在用PKA激活剂鸡尾酒灌流的过程中，钠电流峰值密度显著增加32+/-5.3%(NZs)和17+/-5.4%(IZs)。然而，尽管有这种增加，IZ峰I-Na仍然没有完全恢复到新西兰值。在这两种细胞类型中，密度效应伴随着I/I-max曲线的移动，以及从失活中恢复的缓慢。从关闭状态的失活被加速。此外，在氯喹的存在下，PKA激活剂增加i-Na的作用在NZ仅被部分抑制，而在IZ被取消。为了了解两组细胞的基础Na+通道的磷酸化状态是否不同，研究了冈田酸和PP2A1的作用。结论：PKA刺激重塑的IZs的I-Na可能通过增加通道向膜上活性部位的转运而增加电流密度。然而，所产生的I-Na虽然部分被拯救，但与NZ的强化I-Na并不相似。PKA对IZs的刺激也发生了特定的动力学变化，冈田酸和PP2A1的结果表明，在它们的重塑状态下，IZs中的Na+通道已经被磷酸化了。(C)2004年欧洲心脏病学会。爱思唯尔出版，版权所有。
Objective and methods: In this study, we investigated the effects of a PKA Stimulating cocktail on sodium currents from normal epicardial cells (NZs) and on those from cells dispersed from the epicardial zone of the 5-day infarcted canine heart (IZs). To do so, we used whole-cell voltage-clamp techniques.Results: During superfusion with the PKA activator cocktail, peak sodium current (I-Na) density significantly increased by 32 +/- 5.3% (NZs) and 17 +/- 5.4% (IZs). However, despite this increase, IZ peak I-Na still was not fully restored to NZ values. In both cell types, the density effect was accompanied by a shift in I/I-max curves, as well as a slowing in recovery from inactivation. Inactivation from a closed state was accelerated. Furthermore, in the presence of chloroquine, which is known to interrupt intracellular vesicular traffic, PKA activator effects to augment I-Na were only partially inhibited in NZs but abolished in IZs. To understand whether the phosphorylation status of basal Na+ channels in the two cell groups differed, the effects of okadaic acid and PP2A1 were studied. Results suggest that in IZs, Na+ channels in the basal state are already phosphorylated.Conclusions: PKA stimulation of I-Na of the remodeled IZ does augment current density possibly by augmenting the trafficking of channels to an active site on the membrane. However, the resulting I-Na while partially rescued, is not similar to the potentiated I-Na of NZs. Specific kinetic changes also occur with the PKA stimulation of IZs and results with okadaic acid and PP2A1 suggest that in their remodeled state, Na+ channels in IZs are already phosphorylated. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.