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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway
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CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway

机译：CLOCK-BMAL1通过PI3K-Akt信号通路调节心脏L型钙通道亚基CACNA1C

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摘要

The heterodimerized transcription factors CLOCK-BMAL1 regulate the cardiomyocyte circadian rhythms. The L-type calcium currents play important role in the cardiac electrogenesis and arrhythmogenesis. Whether and how the CLOCK-BMAL1 regulate the cardiac L-type calcium channels are yet to be determined. The functions of the L-type calcium channels were evaluated with patch clamping techniques. Recombinant adenoviruses of CLOCK and BMAL1 were used in the expression experiments. We reported that the expressions and functions of CACNA1C (the alpha-subunit of the L-type calcium channels) showed circadian rhythms, with the peak at zeitgeber time 3 (ZT3). The endocardial action potential durations 90 (APD90) were correspondingly longer at ZT3. The protein levels of the phosphorylated Akt at threonine 308 (pAkt T308) also showed circadian rhythms. Overexpressions of CLOCK-BMAL1 significantly reduced the levels of CACNA1C while increasing the levels of pAkt T308 and pik3r1. Furthermore, the inhibitory effects of CLOCK-BMAL1 on CACNA1C could be abolished by the Akt inhibitor MK2206 or the PDK1 inhibitor GSK2334470. Collectively, our findings suggested that the expressions of the cardiac CACNA1C were under the CLOCK-BMAL1 regulation, probably through the PI3K-Akt signal pathway.
机译：异二聚体转录因子CLOCK-BMAL1调节心肌细胞的昼夜节律。 L型钙电流在心脏电发生和心律失常中起重要作用。 CLOCK-BMAL1是否以及如何调节心脏L型钙通道尚未确定。 L型钙通道的功能已通过膜片钳技术进行了评估。表达实验中使用了CLOCK和BMAL1重组腺病毒。我们报道，CACNA1C（L型钙通道的α-亚基）的表达和功能表现出昼夜节律，在zeitgeber时间3（ZT3）达到峰值。在ZT3，心内膜动作电位持续时间90（APD90）相应更长。苏氨酸308（pAkt T308）磷酸化的Akt的蛋白质水平也显示了昼夜节律。 CLOCK-BMAL1的过表达显着降低了CACNA1C的水平，同时增加了pAkt T308和pik3r1的水平。此外，Akt抑制剂MK2206或PDK1抑制剂GSK2334470可以消除CLOCK-BMAL1对CACNA1C的抑制作用。总的来说，我们的发现表明心脏CACNA1C的表达受CLOCK-BMAL1调控，可能是通过PI3K-Akt信号通路。

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