Journal
CIRCULATION RESEARCH
Volume 109, Issue 5, Pages 512-U150Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.248864
Keywords
calcium signaling; excitation contraction coupling; hypertrophy; mouse; neuronal calcium sensor-1
Funding
- Takeda Science Foundation
- Salt Science Research Foundation [0912]
- Astellas Foundation for Research on Metabolic Disorders [3072]
- [18077015]
- [21590248]
- Grants-in-Aid for Scientific Research [23390046, 21590248, 20220007, 22659046] Funding Source: KAKEN
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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.)
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