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Potentiation of Ca 2+ Release by cADP-Ribose in the Heart Is Mediated by Enhanced SR Ca 2+ Uptake Into the Sarcoplasmic Reticulum

2001; Lippincott Williams & Wilkins; Volume: 89; Issue: 7 Linguagem: Inglês

10.1161/hh1901.098066

1524-4571

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

Adenosine and Purinergic Signaling

Abstract— cADP-Ribose (cADPR) is a novel endogenous messenger that is believed to mobilize Ca 2+ from ryanodine-sensitive Ca 2+ 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 Ca 2+ 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 Ca 2+ sparks. These effects on local release events were accompanied by a significant increase in sarcoplasmic reticulum (SR) Ca 2+ content. In comparison, sensitization of ryanodine receptors (RyRs) by caffeine, a true RyR agonist, caused a rapid (<1 second) and transient potentiation of Ca 2+ sparks followed by a decrease in SR Ca 2+ content. When the increase in the SR load was prevented by partial inhibition of the SR Ca 2+ 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 Ca 2+ uptake by cardiac SR microsomes. Our results suggest that the primary target of cADPR is the SR Ca 2+ uptake mechanism. Potentiation of Ca 2+ release by cADPR is mediated by increased accumulation of Ca 2+ in the SR and subsequent luminal Ca 2+ -dependent activation of RyRs.