The cardiac sodium–calcium exchanger NCX1 is a key player in the initiation and maintenance of a stable heart rhythm

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The complex molecular mechanisms underlying spontaneous cardiac pacemaking are not fully understood. Recent findings point to a co-ordinated interplay between intracellular Ca2+ cycling and plasma membrane-localized cation transport determining the origin and periodicity of pacemaker potentials. The sodium–calcium exchanger (NCX1) is a key sarcolemmal protein for the maintenance of calcium homeostasis in the heart. Here, we investigated the contribution of NCX1 to cardiac pacemaking.

Methods and results

We used an inducible and sinoatrial node-specific Cre transgene to create micelacking NCX1 selectively in cells of the cardiac pacemaking and conduction system (cpNCX1KO). RT–PCR and immunolabeling experiments confirmed the precise tissue-specific and temporally controlled deletion. Ablation of NCX1 resulted in a progressive slowing of heart rate accompanied by severe arrhythmias. Isolated sinoatrial tissue strips displayed a significantly decreased and irregular contraction rate underpinning a disturbed intrinsic pacemaker activity. Mutant animals displayed a gradual increase in the heart-to-body weight ratio and developed ventricular dilatation; however, their ventricular contractile performance was not significantly affected. Pacemaker cells from cpNCX1KO showed no NCX1 activity in response to caffeine-induced Ca2+ release, determined by Ca2+ imaging. Regular spontaneous Ca2+ discharges were frequently seen in control, but only sporadically in knockout (KO) cells. The majority of NCX1KO cells displayed an irregular and a significantly reduced frequency of spontaneous Ca2+ signals. Furthermore, Ca2+ transients measured during electrical field stimulation were of smaller magnitude and decelerated kinetics in KO cells.


Our results establish NCX1 as a critical target for the proper function of cardiac pacemaking.

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