The mechanism of action of digoxin requires the sodium-dependent inactivation of the sodium-calcium exchanger
- Kyle Scranton
- Scott John
- Marina Angelini
- Rui Zhang
- Andreas Schwingshackl
- Joshua I. Goldhaber
- Riccardo Olcese
- Michela Ottolia
2025-12-17
For more than two centuries, digoxin has been used to treat heart failure by increasing the strength of cardiac contraction and, more recently, is used for heart rate control. The proposed, yet unproven, mechanism underlying digoxin’s positive inotropic effect is as follows: By inhibiting the Na + -K + ATPase (NKA), digoxin partially dissipates the transmembrane Na + gradient, which is used by the Na + -Ca 2+ exchanger (NCX1) to extrude Ca 2+ from myocytes, thus causing accumulation of cytosolic Ca 2+ and therefore increased cardiac contractility. Here, we demonstrate that digoxin critically relies on a specific allosteric regulation of NCX1, known as Na + -dependent inactivation, to exert its positive inotropic effect, establishing the precise mechanism of action of this historic drug. These findings identify a distinct molecular target for the development of positive inotropes that avoid the undesirable effects associated with the blockade of NKA. As the structural information for the region involved with NCX1 Na + -dependent inhibition is well resolved, we provide the mechanistic foundation for drug development.