title: Neuronal calcium sensor-1 promotes immature heart function and hypertrophy by enhancing Ca2+ signals.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. tomoen@ri.ncvc.go.jp
authors: Tomoe Y
authors: TY
authors: Nakamura
authors: Andreas
authors: A
authors: Jeromin
authors: Katsuhiko
authors: K
authors: Mikoshiba
authors: Shigeo
authors: S
authors: Wakabayashi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D006321:Heart / Q000254:growth & development*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D051580:Neuronal Calcium-Sensor Proteins / Q000096:biosynthesis / Q000502:physiology*; D009479:Neuropeptides / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; C101464:frequenin calcium sensor proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2