論文

査読有り 筆頭著者
2005年2月

Calcineurin inhibits Na+/Ca2+ exchange in phenylephrine-treated hypertrophic cardiomyocytes

JOURNAL OF BIOLOGICAL CHEMISTRY
  • Y Katanosaka
  • ,
  • Y Iwata
  • ,
  • Y Kobayashi
  • ,
  • F Shibasaki
  • ,
  • S Wakabayashi
  • ,
  • M Shigekawa

280
7
開始ページ
5764
終了ページ
5772
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1074/jbc.M410240200
出版者・発行元
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

The cardiac Na+/Ca2+ exchanger (NCX1) is the predominant mechanism for the extrusion of Ca2+ from beating cardiomyocytes. The role of protein phosphorylation in the regulation of NCX1 function in normal and diseased hearts remains unclear. In our search for proteins that interact with NCX1 using a yeast two-hybrid screen, we found that the C terminus of calcineurin Abeta, containing the autoinhibitory domain, binds to the beta1 repeat of the central cytoplasmic loop of NCX1 that presumably constitutes part of the allosterie Ca2+ regulatory site. The association of NCX1 with calcineurin was significantly increased in the BI014.6 cardiomyopathic hamster heart compared with that in the normal control. In hypertrophic neonatal rat cardiomyocytes subjected to chronic phenylephrine treatment, we observed a marked depression of NCX activity measured as the rate of Na+ i-dependent Ca-45(2+) uptake or the rate of Na+ o-dependent Ca-45(2+) efflux. Depressed NCX activity was partially and independently reversed by the acute inhibition of calcineurin and protein kinase C activities with little effect on myocyte hypertrophic phenotypes. Studies of NCX1 deletion mutants expressed in CCL39 cells were consistent with the view that the beta1. repeat is required for the action of endogenous calcineurin and that the large cytoplasmic loop may be required to maintain the interaction of the enzyme with its substrate. Our data suggest that NCX1 is a novel regulatory target for calcineurin and that depressed NCX activity might contribute to the etiology of in vivo cardiac hypertrophy and dysfunction occurring under conditions in which both calcineurin and protein kinase C are chronically activated.

リンク情報
DOI
https://doi.org/10.1074/jbc.M410240200
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/15557343
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000227217100078&DestApp=WOS_CPL
ID情報
  • DOI : 10.1074/jbc.M410240200
  • ISSN : 0021-9258
  • PubMed ID : 15557343
  • Web of Science ID : WOS:000227217100078

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