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(Circulation Research. 2001;89:614.)
© 2001 American Heart Association, Inc.

Cellular Biology

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

From the Department of Physiology (V.L., I.G., S.G.), Texas Tech University Health Sciences Center, and the Department of Chemical Engineering (T.F.W.), Texas Tech University, Lubbock.

Correspondence to Dr Sandor Györke, Texas Tech University HSC, 3601 4th St, Lubbock, TX 9430-6551. E-mail physg{at}ttuhsc.edu

Abstract — 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.

Key Words: ventricular myocytes • ryanodine receptors • sarcoplasmic reticulum Ca²⁺ • Ca²⁺ sparks • cADP-ribose

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