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Cardiovascular Research Advance Access originally published online on November 5, 2007
Cardiovascular Research 2008 77(2):274-284; doi:10.1093/cvr/cvm058
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Published by Oxford University Press on behalf of the European Society of Cardiology 2007. For permissions please email: journals.permissions@oxfordjournals.org

Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function

Victor A. Maltsev and Edward G. Lakatta*

Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD, USA

* Corresponding author. Tel: +1 410 558 8202; fax: +1 410 558 8150. E-mail address: lakattae{at}grc.nia.nih.gov

For almost half a century it has been thought that the initiation of each heartbeat is driven by surface membrane voltage-gated ion channels (M clocks) within sinoatrial nodal cells. It has also been assumed that pacemaker cell automaticity is initiated at the maximum diastolic potential (MDP). Recent experimental evidence based on confocal cell imaging and supported by numerical modelling, however, shows that initiation of cardiac impulse is a more complex phenomenon and involves yet another clock that resides under the sarcolemma. This clock is the sarcoplasmic reticulum (SR): it generates spontaneous, but precisely timed, rhythmic, submembrane, local Ca2+ releases (LCR) that appear not at the MDP but during the late, diastolic depolarization (DD). The Ca2+ clock and M clock dynamically interact, defining a novel paradigm of robust cardiac pacemaker function and regulation. Rhythmic LCRs during the late DD activate inward Na+/Ca2+ exchanger currents and ignite action potentials, which in turn induceCa2+ transients and SR depletions, resetting the Ca2+ clock. Both basal and reserve protein kinaseA-dependent phosphorylation of Ca2+ cycling proteins control the speed and amplitude of SR Ca2+ cycling to regulate the beating rate by strongly coupled Ca2+ and M clocks.

KEYWORDS Sinus node; SR (function); Calcium (cellular); Na/Ca-exchanger; Ion channels

Time for primary review: 47 days


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