Intracellular na+ modulates pacemaking activity in murine sinoatrial node myocytes: An in silico analysis

Stefano Morotti, Haibo Ni, Colin H. Peters, Christian Rickert, Ameneh Asgari-Targhi, Daisuke Sato, Alexey V. Glukhov, Catherine Proenza, Eleonora Grandi

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca2+-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Car-diomyocyte [Na+]i is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na+ homeostasis in SAN pacemaking and test whether [Na+]i dysregulation may contribute to SAN dysfunction. Methods: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na+ entry (Na+/Ca2+ exchanger, NCX) and removal (Na+/K+ ATPase, NKA). Results: We found that changes in intracellular Na+ homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX-and ankyrin-B-deficient mice due to altered feedback between the Ca2+ and membrane potential clocks underlying SAN firing. Conclusions: Our study gen-erates new testable predictions and insight linking Na+ homeostasis to Ca2+ handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.

Original languageEnglish (US)
Article number5645
JournalInternational journal of molecular sciences
Issue number11
StatePublished - Jun 1 2021


  • Bistability
  • Cardiac arrhythmia
  • Cardiac pacemaking
  • Cardiomyocyte
  • Coupled-clock system
  • Sick sinus syndrome
  • Sinoatrial node
  • Sodium homeostasis
  • Sodium/calcium exchanger
  • Sodium/potassium pump

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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