A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells

Kenta Tsutsui, Oliver J. Monfredi, Syevda G. Sirenko-Tagirova, Larissa A. Maltseva, Rostislav Bychkov, Mary S. Kim, Bruce D. Ziman, Kirill V. Tarasov, Yelena S. Tarasova, Jing Zhang, Mingyi Wang, Alexander V. Maltsev, Jaclyn A. Brennan, Igor R. Efimov, Michael D. Stern, Victor A. Maltsev, Edward Lakatta

Research output: Contribution to journalArticle

Abstract

The spontaneous rhythmic action potentials generated by the sinoatrial node (SAN), the primary pacemaker in the heart, dictate the regular and optimal cardiac contractions that pump blood around the body. Although the heart rate of humans is substantially slower than that of smaller experimental animals, current perspectives on the biophysical mechanisms underlying the automaticity of sinoatrial nodal pacemaker cells (SANCs) have been gleaned largely from studies of animal hearts. Using human SANCs, we demonstrated that spontaneous rhythmic local Ca2+ releases generated by a Ca2+ clock were coupled to electrogenic surface membrane molecules (the M clock) to trigger rhythmic action potentials, and that Ca2+–cAMP–protein kinase A (PKA) signaling regulated clock coupling. When these clocks became uncoupled, SANCs failed to generate spontaneous action potentials, showing a depolarized membrane potential and disorganized local Ca2+ releases that failed to activate the M clock. -Adrenergic receptor (-AR) stimulation, which increases cAMP concentrations and clock coupling in other species, restored spontaneous, rhythmic action potentials in some nonbeating “arrested” human SANCs by increasing intracellular Ca2+ concentrations and synchronizing diastolic local Ca2+ releases. When -AR stimulation was withdrawn, the clocks again became uncoupled, and SANCs reverted to a nonbeating arrested state. Thus, automaticity of human pacemaker cells is driven by a coupled-clock system driven by Ca2+-cAMP-PKA signaling. Extreme clock uncoupling led to failure of spontaneous action potential generation, which was restored by recoupling of the clocks. Clock coupling and action potential firing in some of these arrested cells can be restored by -AR stimulation–induced augmentation of Ca2+-cAMP-PKA signaling.

Original languageEnglish (US)
Article numbereaap7608
JournalScience Signaling
Volume11
Issue number534
DOIs
StatePublished - Jun 12 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Tsutsui, K., Monfredi, O. J., Sirenko-Tagirova, S. G., Maltseva, L. A., Bychkov, R., Kim, M. S., Ziman, B. D., Tarasov, K. V., Tarasova, Y. S., Zhang, J., Wang, M., Maltsev, A. V., Brennan, J. A., Efimov, I. R., Stern, M. D., Maltsev, V. A., & Lakatta, E. (2018). A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells. Science Signaling, 11(534), [eaap7608]. https://doi.org/10.1126/scisignal.aap7608