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Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1

Author

Listed:
  • Kyle Scranton

    (University of California, Los Angeles)

  • Scott John

    (University of California, Los Angeles)

  • Marina Angelini

    (University of California, Los Angeles)

  • Federica Steccanella

    (University of California, Los Angeles)

  • Soban Umar

    (University of California, Los Angeles)

  • Rui Zhang

    (Cedars-Sinai Medical Center)

  • Joshua I. Goldhaber

    (Cedars-Sinai Medical Center)

  • Riccardo Olcese

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Michela Ottolia

    (University of California, Los Angeles)

Abstract

The Na+-Ca2+ exchanger (NCX1) is the dominant Ca2+ extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na+ via a process known as Na+-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function. Using CRISPR/Cas9, we inserted the K229Q mutation in the gene (Slc8a1) encoding for NCX1. This mutation removes the Na+-dependent inactivation while preserving transport properties and other allosteric regulations. NCX1 mRNA levels, protein expression, and protein localization are unchanged in K229Q male mice. However, they exhibit reduced left ventricular ejection fraction and fractional shortening, while displaying a prolonged QT interval. K229Q ventricular myocytes show enhanced NCX1 activity, resulting in action potential prolongation, higher incidence of aberrant action potentials, a faster decline of Ca2+ transients, and depressed cell shortening. The results demonstrate that NCX1 Na+-dependent inactivation plays an essential role in heart function by affecting both cardiac excitability and contractility.

Suggested Citation

  • Kyle Scranton & Scott John & Marina Angelini & Federica Steccanella & Soban Umar & Rui Zhang & Joshua I. Goldhaber & Riccardo Olcese & Michela Ottolia, 2024. "Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47850-z
    DOI: 10.1038/s41467-024-47850-z
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    References listed on IDEAS

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    1. Jing Xue & Weizhong Zeng & Yan Han & Scott John & Michela Ottolia & Youxing Jiang, 2023. "Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
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