TRPC1 channels are critical for hypertrophic signaling in the heart.
TRPC1 channels are critical for hypertrophic signaling in the heart.
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DOI：
10.1161/circresaha.109.206581
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发表时间：
2009-11-06
影响因子：
20.1
通讯作者：
Rosenberg P
中科院分区：
文献类型：
--
作者：
Seth M;Zhang ZS;Mao L;Graham V;Burch J;Stiber J;Tsiokas L;Winn M;Abramowitz J;Rockman HA;Birnbaumer L;Rosenberg P
心肌通过改变心肌细胞的大小和功能来适应增加的工作负荷，从而导致心肌肥大。G蛋白偶联受体(GPCR)信号通过调节衰竭心肌细胞的离子通道活性和下游信号来调控肥大反应。瞬时受体电位通道(TRPC)是以前与心肌肥厚有关的GPCR型通道。我们这项研究的目标是更好地了解TRPC通道如何影响心肌细胞钙信号。在这里，我们使用成年心肌细胞的全细胞膜片钳来显示非选择性阳离子电流的上调，这让人想起压力过载下的TRPC通道。这种TRPC电流对应于压力超负荷小鼠心脏中TRPC通道表达的增加。重要的是，我们发现缺乏TRPC1通道的小鼠丢失了这一假定的TRPC电流。此外，Trpc1−/−小鼠在受到血流动力学压力和神经激素过剩的情况下，未能表现出适应性不良的心肌肥大证据，并保持保存的心脏功能。此外，我们还为Trpc1−/−小鼠通过钙调神经磷酸酶/NFAT、mTOR和Akt的机械敏感信号的改变提供了保护的机制基础。Trpc1−/−小鼠的机制可能是通过钙调神经磷酸酶/NFAT、mTOR和Akt改变。从这些研究中，我们认为TRPC1通道在生物力学应激适应中起关键作用，TRPC调节失调会导致适应性不良的心肌肥厚和衰竭。
Cardiac muscle adapts to increased workload by altering cardiomyocyte size and function resulting in cardiac hypertrophy. G-protein coupled receptor (GPCR) signaling is known to govern the hypertrophic response through the regulation of ion channel activity and downstream signaling in failing cardiomyocytes. Transient receptor potential canonical (TRPC) channels are GPCR operated channels previously implicated in cardiac hypertrophy. Our objective of this study is to better understand how TRPC channels influence cardiomyocyte calcium signaling. Here, we used whole cell patch clamp of adult cardiomyocytes to show upregulation of a non-selective cation current reminiscent of TRPC channels subjected to pressure overload. This TRPC current corresponds to the increased TRPC channel expression noted in hearts of mice subjected to pressure overload. Importantly, we show that mice lacking TRPC1 channels are missing this putative TRPC current. Moreover, Trpc1−/− mice fail to manifest evidence of maladaptive cardiac hypertrophy and maintain preserved cardiac function when subjected to hemodynamic stress and neurohormonal excess. In addition, we provide a mechanistic basis for the protection conferred to Trpc1−/− mice as mechanosensitive signaling through calcineurin/NFAT, mTOR and Akt is altered in Trpc1−/− mice. From these studies, we suggest that TRPC1 channels are critical for the adaptation to biomechanical stress and TRPC dysregulation leads to maladaptive cardiac hypertrophy and failure.