Neuronal Calcium Sensor-1 Promotes Immature Heart Function and Hypertrophy by Enhancing Ca 2+ Signals

Abstract

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 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. Conclusions: 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.