What keeps us ticking: a funny current, a calcium clock, or both?

Edward G. Lakatta, Dario DiFrancesco

Research output: Contribution to journalComment/debatepeer-review

185 Scopus citations


On the basis of prolific experimental evidence supported by novel numerical modeling, it is reasonable to conclude that the tightly coupled system of SR Ca2+ cycling and surface membrane proteins is the clock that controls SANC normal automaticity, leading to their mutual functional entrainment [115]. The clock is robust because the same factors that regulate SR Ca2+ cycling, i.e., Ca2+ and PKA and CaMKII-dependent protein phosphorylation, also regulate sarcolemmal ion channel function and thereby couple SR Ca2+ cycling to the surface membrane. G protein-coupled receptor signaling ensures pacemaker flexibility by affecting rate regulation by impacting on the very same factors that ensure pacemaker fail-safe operation or robustness in a given steady state. Intimately intertwined robustness and flexibility of the heart's pacemaker ensure a wide range of stable heart rates. Rebuttal: DiFrancesco. Ed, you concentrate on the existence of a complex cellular machinery underlying Ca2+ cycling. I have no problem with this, but we are discussing here the function of Ca2+ cycling and that of the funny current. Clearly, none of the mechanisms working in a pacemaker cell can be functionally removed without major impact on the whole behaviour of the cell. Normal physiological pacemaking depends on the integrity of all participating cellular processes, and pointing out that one mechanism is essential for rate control does not mean that mechanism is responsible for that control. The questions we need to address here are simpler ones: which is the physiological process selected to generate spontaneous activity (or, better, discriminating between pacing and silent cardiomyocytes)? Also, when a change in rate is required, which is the physiological process selected, typically by the autonomic nervous system, to produce it? A change in the rate of Ca2+ fluctuations, or a change in If?

Original languageEnglish (US)
Pages (from-to)157-170
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Issue number2
StatePublished - Aug 2009
Externally publishedYes


  • Ca cycling
  • HCN channels
  • HCN4 channelopathies
  • I current
  • I, I, I
  • SERCA-2 Ryanodine receptors
  • biological pacemaker
  • cAMP
  • cardiac pacemaker cells
  • diastolic depolarization
  • funny channels
  • heart rate
  • ion channels
  • ivabradine
  • pacemaker
  • phospholamban
  • protein kinase A-depdendent phosphorylation
  • sinus bradycardia
  • β-adrenergic receptor stimulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'What keeps us ticking: a funny current, a calcium clock, or both?'. Together they form a unique fingerprint.

Cite this