A novel Ca²⁺ regulatory mechanism specific for immature hearts and its potential as a therapeutic target

• Nakamura-Nishitani Tomoe Y.

  Department of Pharmacology, Wakayama-Medical University

Bibliographic Information

Other Title

• 小児特有の心筋細胞内Ca^2＋シグナル調節機構とその治療標的としての可能性
• 小児特有の心筋細胞内Ca²⁺シグナル調節機構とその治療標的としての可能性
• ショウニ トクユウ ノ シンキン サイボウ ナイ Ca²⁺ シグナル チョウセツ キコウ ト ソノ チリョウ ヒョウテキ ト シテ ノ カノウセイ

Abstract

Intracellular Ca²⁺ plays pivotal roles in cardiac contraction by mediating excitation-contraction (EC) coupling and progression of hypertrophy in the heart. Ample evidence suggests that mechanism of EC coupling in immature hearts are different from those in the adults because of the structural immaturity of the sarcoplasmic reticulum (SR) intracellular Ca²⁺ store and the different expression of Ca²⁺-regulatory proteins. However, the detailed molecular mechanism is not completely understood. In the present study, we identified neuronal Ca²⁺ sensor-1 (NCS-1), an EF-hand Ca²⁺ binding protein that is important for neuronal functions, also functions as a novel regulator of EC coupling in young hearts. We found that NCS-1 is highly expressed in immature hearts, and its deletion decreased their contractile functions as well as intracellular Ca²⁺ signals. NCS-1 enhances Ca²⁺ signals mainly by promoting the Inositol 1,4,5-Trisphosphate receptor (IP₃R) function, followed by Ca²⁺/Calmodulin-dependent Protein Kinase II (CaMKII) signaling, which results in a large increase in the SR Ca²⁺ content that enhances SR-dependent EC coupling. In addition, NCS-1 expression increases in the early stages of hypertrophy and promotes progression of hypertrophy at least in part through IP₃R-dependent elevation of nuclear Ca²⁺ signaling. Our results reveal a previously unrecognized mechanism of EC coupling in young heart and the progression of cardiac hypertrophy. Furthermore, we found that NCS-1 contributes to stress tolerance in cardiomyocytes via activation of mitochondrial detoxification pathways. We propose that the proteins involved in NCS-1-mediated Ca²⁺ signaling can be novel therapeutic targets for cardiac diseases, especially in immature hearts.

Journal

• Folia Pharmacologica Japonica

  Folia Pharmacologica Japonica 156 (6), 346-350, 2021

  The Japanese Pharmacological Society

Keywords

• 幼少期
• ECカップリング
• カルシウムセンサー
• 心肥大
• 核内カルシウム

Details

• CRID: 1390289920604415360
• NII Article ID: 130008109931
• NII Book ID: AN00198335
• DOI: 10.1254/fpj.21056
• ISSN: 13478397
• ISSN: 00155691
• NDL BIB ID: 031817354
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I031817354
• Web Site: https://www.jstage.jst.go.jp/article/fpj/156/6/156_21056/_pdf
• Text Lang: ja
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed