Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
Circ Res. 2011 Aug 19;109(5):512-23. doi: 10.1161/CIRCRESAHA.111.248864. Epub 2011 Jul 7.
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.
This study aimed to identify the physiological and pathological roles of NCS-1 in the heart.
We characterized the cardiac functions of knockout mice (Ncs1(-/-)) and identified NCS-1 as a novel regulator of cardiac Ca(2+) 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 Ca(2+) levels and sarcoplasmic reticulum Ca(2+) content were significantly lower in Ncs1(-/-) myocytes than in wild-type cells. This was due to reduced Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity in Ncs1(-/-) myocytes, which led to reduced sarcoplasmic reticulum Ca(2+) uptake and release. NCS-1 physically and functionally interacted with inositol 1,4,5-trisphosphate receptors (IP(3)Rs) in the heart. In addition, IP(3)R stimulation resulted in phosphorylation of CaMKII-δ, which was enhanced by NCS-1 overexpression. These results suggest that a functional link exists between NCS-1, IP(3)R function, and CaMKII activation that may affect global Ca(2+) 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.
NCS-1 is an important regulator of immature heart function and hypertrophy, and it functions in part by promoting IP(3)R function, followed by CaMKII-dependent signal activation.
神经元钙传感器-1（NCS-1）调节各种神经元功能。尽管它在心脏中表达，但对其心脏功能知之甚少。
本研究旨在确定 NCS-1 在心脏中的生理和病理作用。
我们对敲除小鼠（Ncs1（-/-））的心脏功能进行了表征，并确定 NCS-1 是心脏 Ca（2+）信号的新型调节剂，特别是在未成熟和肥大的心脏中。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。Ncs1（-/-）心肌细胞中的细胞内 Ca（2+）水平和肌浆网 Ca（2+）含量明显低于野生型细胞。这是由于 Ncs1（-/-）心肌细胞中的 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 在心脏中与肌醇 1,4,5-三磷酸受体（IP（3）R）物理和功能相互作用。此外，IP（3）R 刺激导致 CaMKII-δ磷酸化，而 NCS-1 的过表达增强了这一作用。这些结果表明，NCS-1、IP（3）R 功能和 CaMKII 激活之间存在功能联系，这可能会影响未成熟心脏的整体 Ca（2+）信号。此外，NCS-1 在肥大的心脏中上调，并且激素诱导的肥大在 Ncs1（-/-）心脏中基本得到预防。IP（3）R、CaMKII 和钙调神经磷酸酶抑制剂均能预防 NCS-1 诱导的肥大，这表明这些途径参与其中。
NCS-1 是未成熟心脏功能和肥大的重要调节因子，它的部分功能是通过促进 IP（3）R 功能，随后激活 CaMKII 依赖性信号来实现的。
