title: The cardiac sodium-calcium exchanger NCX1 is a key player in the initiation and maintenance of a stable heart rhythm.
abstract: OBJECTIVE
  The complex molecular mechanisms underlying spontaneous cardiac pacemaking are not fully understood. Recent findings point to a co-ordinated interplay between intracellular Ca(2+) 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.
  
  
  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 Ca(2+) release, determined by Ca(2+) imaging. Regular spontaneous Ca(2+) 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 Ca(2+) signals. Furthermore, Ca(2+) transients measured during electrical field stimulation were of smaller magnitude and decelerated kinetics in KO cells.
  
  
  CONCLUSIONS
  Our results establish NCX1 as a critical target for the proper function of cardiac pacemaking.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. herrmann@pharmakologie.uni-erlangen.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Herrmann
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.forename: Kathrina
authors.initials: K
authors.lastname: Wiesen
authors.forename: Juliane
authors.initials: J
authors.lastname: Stieber
authors.forename: Huong
authors.initials: H
authors.lastname: Nguyen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kaiser
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D002118:Calcium / Q000378:metabolism; D006339:Heart Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D012849:Sinoatrial Node / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000502:physiology*; D020257:Ventricular Remodeling
chemical_list: C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D002118:Calcium
keywords: Cardiac pacemaking; Sinoatrial node