Synchronization of stochastic Ca2+ release units creates a rhythmic Ca2+ clock in cardiac pacemaker cells

Anna V. Maltsev, Victor A. Maltsev, Maxim Mikheev, Larissa A. Maltseva, Syevda G. Sirenko, Edward G. Lakatta, Michael D. Stern

Research output: Contribution to journalArticle

Abstract

In sinoatrial node cells of the heart, beating rate is controlled, in part, by local Ca2+ releases (LCRs) from the sarcoplasmic reticulum, which coupletothe action potential via electrogenic Na+/Ca 2+exchange.Weobserved persisting, roughlyperiodic LCRs indepolarized rabbit sinoatrial node cells (SANCs). The featuresofthese LCRs were reproduced by a numerical model consisting of a two-dimensional array of stochastic, diffusively coupled Ca2+ release units (CRUs) with fixed refractory period. Because previous experimental studies showed that β-adrenergic receptor stimulation increases the rateof Ca2+ release through each CRU (dubbed Ispark), we explored the link between LCRs and I spark in our model. Increasing the CRU release current I spark facilitated Ca2+-induced-Ca2+ release and local recruitment of neighboring CRUs to fire more synchronously. This resulted in a progression in simulated LCR size (from sparks to wavelets to global waves), LCR rhythmicity, and decrease of LCR period that parallels the changes observed experimentally with β-adrenergic receptor stimulation. The transition in LCR characteristics was steeply nonlinear over a narrow range of Ispark, resembling a phase transition. We conclude that the (partial) periodicity and rate regulation of the "Calcium clock" in SANCs are emergent properties of the diffusive coupling of an ensemble of interacting stochastic CRUs. The variation in LCR period and size with Ispark is sufficient to account for β-adrenergic regulation of SANC beating rate.

Original languageEnglish (US)
Pages (from-to)271-283
Number of pages13
JournalBiophysical journal
Volume100
Issue number2
DOIs
StatePublished - Jan 19 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biophysics

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    Maltsev, A. V., Maltsev, V. A., Mikheev, M., Maltseva, L. A., Sirenko, S. G., Lakatta, E. G., & Stern, M. D. (2011). Synchronization of stochastic Ca2+ release units creates a rhythmic Ca2+ clock in cardiac pacemaker cells. Biophysical journal, 100(2), 271-283. https://doi.org/10.1016/j.bpj.2010.11.081