A Simulation Study to Rescue the Na〔+〕/Ca〔2+〕 Exchanger Knockout Mice

• Sarai Nobuaki

  Department of Physiology and Biophysics, Graduate School of Medicine, Kyoto University

• Kobayashi Tsutomu

  Pharmacological Research Laboratory, Tanabe Seiyaku Co., Ltd.

• Matsuoka Satoshi

  Department of Physiology and Biophysics, Graduate School of Medicine, Kyoto University

• Noma Akinori

  Department of Physiology and Biophysics, Graduate School of Medicine, Kyoto University

書誌事項

タイトル別名

• A Simulation Study to Rescue the Na+/Ca2+ Exchanger Knockout Mice
• Simulation Study to Rescue the Na Ca 2 Exchanger Knockout Mice

抄録

The Na⁺/Ca²⁺ exchanger (NCX) is the major Ca²⁺ efflux system in cardiac myocytes, and thereby its global knockout is embryonically lethal. However, Henderson et al. (2004) found that mice with the cardiospecific knockout of NCX1 lived to adulthood. No adaptation was detected in expression levels of other proteins except for a 50% reduction in the L-type Ca²⁺ current (I_CaL) as revealed in electrophysiological studies. To predict mechanisms of survival, we simulated cardiac myocyte activity in the absence of NCX using a mathematical model of guinea pig ventricular myocytes. The NCX knockout resulted in contracture of the model cell because of a rise in the cytoplasmic Ca²⁺ ([Ca²⁺]_i). However, up-regulation of the sarcolemmal Ca²⁺ pump (PMCA) and/or down-regulation of I_CaL enables steady rhythmic contractions even if NCX is totally excluded. The simulation predicted that the steady activities are maintained by a functional up-regulation of PMCA by about 2.3 times in addition to the down-regulation of I_CaL to a half, as observed in the experiment. However, the model analysis predicted that the myocyte depending on PMCA for Ca²⁺ extrusion is unstable against any changes in ionic fluxes and energetically unfavorable in comparison with the control. The reason for the instability is that the activity of PMCA driven by the ATP hydrolysis is hardly affected by changes in [Ca²⁺]_i, but NCX has a reversal potential in the middle level of the action potential and is immediately affected by the Ca²⁺ flux via NCX itself. The source code of the model is available at http://www.sim-bio.org/.<br>

収録刊行物

• The Journal of Physiological Sciences

  The Journal of Physiological Sciences 56 (3), 211-217, 2006

  一般社団法人　日本生理学会

キーワード

• Na⁺/Ca²⁺ exchanger
• NCX1
• sarcolemmal Ca²⁺ pump

詳細情報

• CRID: 1390001205252280960
• NII論文ID: 10020331558
• NII論文ID: 130004466847
• NII書誌ID: AA12129145
• DOI: 10.2170/physiolsci.rp005006
• ISSN: 18806562
• ISSN: 18806546
• NDL書誌ID: 8046908
• PubMed: 16839455
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I8046908
• Web Site: https://search.jamas.or.jp/link/ui/2007087762
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
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