Recovery of cardiac calcium release is controlled by sarcoplasmic reticulum refilling and ryanodine receptor sensitivity

Cardiovasc Res. 2011 Sep 1;91(4):598-605. doi: 10.1093/cvr/cvr143. Epub 2011 May 24.


Aims: In heart cells, the mechanisms underlying refractoriness of the elementary units of sarcoplasmic reticulum (SR) Ca(2+) release, Ca(2+) sparks, remain unclear. We investigated local recovery of SR Ca(2+) release using experimental measurements and mathematical modelling.

Methods and results: Repeated Ca(2+) sparks were induced from individual clusters of ryanodine receptors (RyRs) in quiescent rat ventricular myocytes, and we examined how changes in RyR gating influenced the time-dependent recovery of Ca(2+) spark amplitude and triggering probability. Repeated Ca(2+) sparks from individual sites were analysed in the presence of 50 nM ryanodine with: (i) no additional agents (control); (ii) 50 µM caffeine to sensitize RyRs; (iii) 50 µM tetracaine to inhibit RyRs; or (iv) 100 nM isoproterenol to activate β-adrenergic receptors. Sensitization and inhibition of RyR clusters shortened and lengthened, respectively, the median interval between consecutive Ca(2+) sparks (caffeine 239 ms; control 280 ms; tetracaine 453 ms). Recovery of Ca(2+) spark amplitude, however, was exponential with a time constant of ∼100 ms in all cases. Isoproterenol both accelerated the recovery of Ca(2+) spark amplitude (τ = 58 ms) and shortened the median interval between Ca(2+) sparks (192 ms). The results were recapitulated by a mathematical model in which SR [Ca(2+)] depletion terminates Ca(2+) sparks, but not by an alternative model based on limited depletion and Ca(2+)-dependent inactivation of RyRs.

Conclusion: Together, the results strongly suggest that: (i) local SR refilling controls Ca(2+) spark amplitude recovery; (ii) Ca(2+) spark triggering depends on both refilling and RyR sensitivity; and (iii) β-adrenergic stimulation influences both processes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calsequestrin / physiology
  • Computer Simulation
  • Isoproterenol / pharmacology
  • Male
  • Myocardium / metabolism*
  • Rats
  • Ryanodine / pharmacology
  • Ryanodine Receptor Calcium Release Channel / physiology*
  • Sarcoplasmic Reticulum / metabolism*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / physiology


  • Calsequestrin
  • Ryanodine Receptor Calcium Release Channel
  • Ryanodine
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Isoproterenol
  • Calcium