Potentiation of Ca2+ release by cADP-Ribose in the heart is mediated by enhanced SR Ca2+ uptake into the sarcoplasmic reticulum

Valeriy Lukyanenko, Inna Györke, Theodore F. Wiesner, Sandor Györke

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55 Scopus citations


cADP-Ribose (cADPR) is a novel endogenous messenger that is believed to mobilize Ca2+ from ryanodine-sensitive Ca2+ stores. Despite intense research, the precise mechanism of action of cADPR remains uncertain, and experimental findings are contradictory. To elucidate the mechanism of cADPR action, we performed confocal Ca2+ imaging in saponin-permeabilized rat ventricular myocytes. Exposure of the cells to cADPR resulted in a slow (>2 minutes) and steady increase in the frequency of Ca2+ sparks. These effects on local release events were accompanied by a significant increase in sarcoplasmic reticulum (SR) Ca2+ content. In comparison, sensitization of ryanodine receptors (RyRs) by caffeine, a true RyR agonist, caused a rapid (< 1 second) and transient potentiation of Ca2+ sparks followed by a decrease in SR Ca2+ content. When the increase in the SR load was prevented by partial inhibition of the SR Ca2+ with thapsigargin, cADPR failed to produce any increase in sparking activity. cADPR had no significant impact on activity of single cardiac RyRs incorporated into lipid bilayers. However, it caused a significant increase in the rate of Ca2+ uptake by cardiac SR microsomes. Our results suggest that the primary target of cADPR is the SR Ca2+ uptake mechanism. Potentiation of Ca2+ release by cADPR is mediated by increased accumulation of Ca2+ in the SR and subsequent luminal Ca2+-dependent activation of RyRs.

Original languageEnglish
Pages (from-to)614-622
Number of pages9
JournalCirculation Research
Issue number7
StatePublished - Sep 28 2001


  • Ca sparks
  • Ryanodine receptors
  • Sarcoplasmic reticulum Ca
  • Ventricular myocytes
  • cADP-ribose


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