Functional modulation of sarcolemmal KATP channels by atrial natriuretic peptide-elicited intracellular signaling in adult rabbit ventricular cardiomyocytes.
Functional modulation of sarcolemmal KATP channels by atrial natriuretic peptide-elicited intracellular signaling in adult rabbit ventricular cardiomyocytes.
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心房钠尿肽引起成年兔心室心肌细胞内信号传导对肌膜 KATP 通道的功能调节。
DOI：
10.1152/ajpcell.00409.2019
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Lin,Yu-Fung
中科院分区：
文献类型：
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作者：
Zhang,Dai-Min;Lin,Yu-Fung
ATP 敏感钾 (KATP) 通道将细胞代谢状态与膜兴奋性结合起来，对于心脏的应激适应和细胞保护至关重要。心房钠尿肽 (ANP) 是一种对心血管稳态很重要的心脏肽，还具有细胞保护功能，包括防止心肌缺血再灌注损伤。然而，ANP 如何调节心脏 KATP 通道尚不清楚。在本研究中，我们试图通过研究 ANP 信号传导在从成年兔心脏新鲜分离的心室肌细胞中肌膜 KATP（sarcKATP）通道功能调节中的作用来解决这个问题。单通道记录与细胞贴附贴片配置中的药理学方法相结合进行。 ANP 的沐浴应用显着增强了叠氮化钠代谢抑制诱导的 sarcKATP 通道活性，而 ANP 的 KATP 刺激作用则通过选择性抑制 A 型利钠肽受体 (NPR-A)、cGMP 依赖性蛋白激酶 (PKG)、活性氧 (ROS)、细胞外酶而消除。 信号调节蛋白激酶 (ERK)1/2、Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 或兰尼碱受体 (RyR)。阻断 RyR 还可以消除过氧化氢 (H2O2) 诱导的完整细胞中 sarKATP 通道的刺激。此外，单通道动力学分析表明，ANP 通过破坏长闭合的稳定性并促进开放转换来增强心室肌 KATP 通道的功能，而不影响单通道电导。总之，我们在此报告 ANP 通过由 NPR-A、PKG、ROS、ERK1/2、CaMKII 和 RyR2 组成的细胞内信号传导机制正向调节心室肌 KATP 通道的活性。这种新机制可能部分通过打开心肌 KATP 通道来调节心脏兴奋性并有助于细胞保护。
ATP-sensitive potassium (KATP) channels couple cell metabolic status to membrane excitability and are crucial for stress adaptation and cytoprotection in the heart. Atrial natriuretic peptide (ANP), a cardiac peptide important for cardiovascular homeostasis, also exhibits cytoprotective features including protection against myocardial ischemia-reperfusion injuries. However, how ANP modulates cardiac KATPchannels is largely unknown. In the present study we sought to address this issue by investigating the role of ANP signaling in functional modulation of sarcolemmal KATP(sarcKATP) channels in ventricular myocytes freshly isolated from adult rabbit hearts. Single-channel recordings were performed in combination with pharmacological approaches in the cell-attached patch configuration. Bath application of ANP markedly potentiated sarcKATPchannel activities induced by metabolic inhibition with sodium azide, whereas the KATP-stimulating effect of ANP was abrogated by selective inhibition of the natriuretic peptide receptor type A (NPR-A), cGMP-dependent protein kinase (PKG), reactive oxygen species (ROS), extracellular signal-regulated protein kinase (ERK)1/2, Ca2+/calmodulin-dependent protein kinase II (CaMKII), or the ryanodine receptor (RyR). Blockade of RyRs also nullified hydrogen peroxide (H2O2)-induced stimulation of sarcKATPchannels in intact cells. Furthermore, single-channel kinetic analyses revealed that ANP enhanced the function of ventricular sarcKATPchannels through destabilizing the long closures and facilitating the opening transitions, without affecting the single-channel conductance. In conclusion, here we report that ANP positively modulates the activity of ventricular sarcKATPchannels via an intracellular signaling mechanism consisting of NPR-A, PKG, ROS, ERK1/2, CaMKII, and RyR2. This novel mechanism may regulate cardiac excitability and contribute to cytoprotection, in part, by opening myocardial KATPchannels.