Neuronal calcium sensor-1 promotes immature heart function and hypertrophy by enhancing Ca2+ signals

Circ Res. 2011 Aug 19;109(5):512-23. doi: 10.1161/CIRCRESAHA.111.248864. Epub 2011 Jul 7.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Calcium Signaling / physiology*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology*
  • Cardiomegaly / prevention & control
  • Heart / growth & development*
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism*
  • Neuronal Calcium-Sensor Proteins / biosynthesis
  • Neuronal Calcium-Sensor Proteins / physiology*
  • Neuropeptides / biosynthesis
  • Neuropeptides / physiology*
  • Up-Regulation / genetics

Substances

  • Inositol 1,4,5-Trisphosphate Receptors
  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides
  • frequenin calcium sensor proteins
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2