AIM The enzyme 3-phosphoinositide-dependent protein kinase-1 (PDK1) is associated with cardiac and pathological remodeling and ion channel function regulation. However, whether it regulates hyperpolarization-activated cyclic nucleotide-modulated channels (HCNs) remains unclear. MAIN METHODS In the atrial myocytes of heart-specific PDK1 "knockout" mouse model and neonatal mice, protein kinase B (AKT)-related inhibitors or agonists as well as knockdown or overexpression plasmids were used to study the relationship between PDK1 and HCNs. KEY FINDINGS HCN1 expression and AKT phosphorylation at the Thr308 site were significantly decreased in atrial myocytes after PDK1 knockout or inhibition; in contrast, HCN2 and HCN4 levels were significantly increased. Also, a similar trend of HCNs expression has been observed in cultured atrial myocytes after PDK1 inhibition, as further demonstrated via immunofluorescence and patch-clamp experiments. Moreover, these results of PDK1 overexpression indicate an opposite trend compared with the previous experimental results. However, the results of PDK1 inhibition or overexpression could be reversed by activating or inhibiting AKT, respectively. SIGNIFICANCE These results indicate that the PDK1-AKT signaling pathway is involved in the regulation of HCN mRNA transcription, protein expression, HCN current density, and cell membrane location.

中文翻译：

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PDK1-AKT信号通路调节心脏超极化激活的环状核苷酸调节通道的表达和功能。

目的酶3-磷酸肌醇依赖性蛋白激酶-1（PDK1）与心脏和病理重塑以及离子通道功能调节相关。然而，是否调节超极化激活的环状核苷酸调节通道（HCNs）仍不清楚。主要方法在心脏特异性PDK1“敲除”小鼠模型和新生小鼠的心房肌细胞中，使用蛋白激酶B（AKT）相关的抑制剂或激动剂以及敲低或过表达质粒来研究PDK1和HCN之间的关系。主要发现在PDK1敲除或抑制后，心房肌细胞中Thr308位点的HCN1表达和AKT磷酸化显着降低。相反，HCN2和HCN4水平显着增加。也，PDK1抑制后，在培养的心房肌细胞中观察到了类似的HCNs表达趋势，这一点已通过免疫荧光和膜片钳实验进一步证实。而且，与先前的实验结果相比，PDK1过表达的这些结果表明了相反的趋势。但是，分别通过激活或抑制AKT可以逆转PDK1抑制或过表达的结果。意义这些结果表明，PDK1-AKT信号通路参与HCN mRNA转录，蛋白质表达，HCN电流密度和细胞膜位置的调节。通过激活或抑制AKT可以逆转PDK1抑制或过表达的结果。意义这些结果表明，PDK1-AKT信号通路参与HCN mRNA转录，蛋白质表达，HCN电流密度和细胞膜位置的调节。PDK1抑制或过表达的结果可以分别通过激活或抑制AKT来逆转。意义这些结果表明，PDK1-AKT信号通路参与HCN mRNA转录，蛋白质表达，HCN电流密度和细胞膜位置的调节。