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

Kyle Scranton, Scott John, Marina Angelini, Federica Steccanella, Soban Umar, Rui Zhang, Joshua I. Goldhaber, Riccardo Olcese and Michela Ottolia ()
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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
Michela Ottolia: University of California, Los Angeles

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47850-z

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