Neuronal Calcium Sensor-1 Promotes Immature Heart Function and Hypertrophy by Enhancing Ca2+ Signals
Neuronal Calcium Sensor-1 Promotes Immature Heart Function and Hypertrophy by Enhancing Ca2+ Signals
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DOI：
10.1161/circresaha.111.248864
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发表时间：
2011-08-19
影响因子：
20.1
通讯作者：
Wakabayashi, Shigeo
中科院分区：
文献类型：
--
作者：
Nakamura, Tomoe Y.;Jeromin, Andreas;Wakabayashi, Shigeo
神经元钙传感器-1（NCS-1）调节多种神经元功能。虽然它是在心脏中表达，很少知道它的cardiac functions.Objective：这项研究旨在确定NCS-1在heart.Methods和Results的生理和病理作用：我们的特点是敲除小鼠（NCS 1（-/-））的心脏功能，并确定NCS-1作为一种新的调节心脏Ca 2+信号，特别是在未成熟和肥大的心脏。NCS-1在年轻的心脏中高度表达，其缺失降低了年轻小鼠的存活率和收缩功能。Ncs 1（-/-）心肌细胞胞内Ca 2+水平和肌浆网Ca 2+含量显著低于野生型细胞。这是由于Ncs 1（-/-）肌细胞中Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）活性降低，导致肌浆网Ca 2+摄取和释放减少。NCS-1与心脏中的1，4，5-三磷酸肌醇受体（IP（3）Rs）在物理和功能上相互作用。此外，IP 3R刺激导致CaMKII-δ的磷酸化，其通过NCS-1过表达而增强。这些结果表明，NCS-1，IP 3R功能和CaMKII激活之间存在功能联系，可能会影响未成熟心脏中的全局Ca 2+信号。此外，NCS-1在肥大心脏中上调，并且在Ncs 1（-/-）心脏中很大程度上防止了心脏肥大。IP（3）Rs、CaMKII和钙调神经磷酸酶抑制剂均能阻止NCS-1诱导的心肌肥厚，这表明这些通路参与其中。结论：NCS-1是不成熟心脏功能和心肌肥厚的重要调节因子，其部分功能是通过促进IP（3）Rs功能，随后是CaMKII依赖的信号激活。(Circ Res. 2011; 109：512-523）。
Rationale: Neuronal calcium sensor-1 (NCS-1) regulates various neuronal functions. Although it is expressed in the heart, very little is known about its cardiac functions.Objective: This study aimed to identify the physiological and pathological roles of NCS-1 in the heart.Methods and Results: We characterized the cardiac functions of knockout mice (Ncs1(-/-)) and identified NCS-1 as a novel regulator of cardiac Ca2+ signaling, specifically in immature and hypertrophic hearts. NCS-1 was highly expressed in young hearts, and its deletion decreased survival and contractile function in young mice. Intracellular Ca2+ levels and sarcoplasmic reticulum Ca2+ content were significantly lower in Ncs1(-/-) myocytes than in wild-type cells. This was due to reduced Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity in Ncs1(-/-) myocytes, which led to reduced sarcoplasmic reticulum Ca2+ uptake and release. NCS-1 physically and functionally interacted with inositol 1,4,5-trisphosphate receptors (IP(3)Rs) in the heart. In addition, IP3R stimulation resulted in phosphorylation of CaMKII-delta, which was enhanced by NCS-1 overexpression. These results suggest that a functional link exists between NCS-1, IP3R function, and CaMKII activation that may affect global Ca2+ signals in the immature heart. Furthermore, NCS-1 was upregulated in hypertrophic hearts, and hormone-induced hypertrophy was largely prevented in Ncs1(-/-) hearts. Inhibitors of IP(3)Rs, CaMKII, and calcineurin all prevented NCS-1-induced hypertrophy, which suggests the involvement of these pathways.Conclusions: NCS-1 is an important regulator of immature heart function and hypertrophy, and it functions in part by promoting IP3R function, followed by CaMKII-dependent signal activation. (Circ Res. 2011; 109: 512-523.)