Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling
Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling
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DOI：
10.1074/jbc.m605536200
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发表时间：
2006-11-03
影响因子：
4.8
通讯作者：
McKinsey, Timothy A.
中科院分区：
文献类型：
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作者：
Bush, Erik W.;Hood, David B.;McKinsey, Timothy A.
钙/钙调素依赖性磷酸酶钙调神经磷酸酶在响应于病理刺激的心肌细胞肥大的控制中起核心作用。虽然钙调神经磷酸酶在正常心脏中以高水平存在，但其活性似乎在心动周期过程中不受钙的影响。钙调神经磷酸酶在病理条件下被钙选择性激活的机制仍不清楚。在这里，我们证明了不同的信号心脏肥大刺激典型瞬时受体电位（TRPC）通道的表达。TRPC由七个跨膜非选择性阳离子通道家族组成，这些通道与响应G蛋白偶联受体信号传导、受体酪氨酸激酶信号传导和内部钙储存耗尽的非电压门控钙内流有关。TRPC 3表达在多种病理性心脏肥大的啮齿动物模型中上调，而TRPC 5表达在衰竭的人类心脏中被诱导。我们证明TRPC通过激活钙调神经磷酸酶及其下游效应物，活化T细胞核因子转录因子，促进心肌细胞肥大。这些结果定义了TRPC通道在控制心脏生长中的新作用，并表明TRPC衍生的钙池有助于在患病心脏中选择性激活钙调神经磷酸酶。
The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in the control of cardiomyocyte hypertrophy in response to pathological stimuli. Although calcineurin is present at high levels in normal heart, its activity appears to be unaffected by calcium during the course of a cardiac cycle. The mechanism(s) whereby calcineurin is selectively activated by calcium under pathological conditions has remained unclear. Here, we demonstrate that diverse signals for cardiac hypertrophy stimulate expression of canonical transient receptor potential (TRPC) channels. TRPC consists of a family of seven membrane-spanning nonselective cation channels that have been implicated in the nonvoltage-gated influx of calcium in response to G protein-coupled receptor signaling, receptor tyrosine kinase signaling, and depletion of internal calcium stores. TRPC3 expression is up-regulated in multiple rodent models of pathological cardiac hypertrophy, whereas TRPC5 expression is induced in failing human heart. We demonstrate that TRPC promotes cardiomyocyte hypertrophy through activation of calcineurin and its downstream effector, the nuclear factor of activated T cells transcription factor. These results define a novel role for TRPC channels in the control of cardiac growth, and suggest that a TRPC-derived pool of calcium contributes to selective activation of calcineurin in diseased heart.