TY - JOUR
T1 - Potentiation of Ca2+ release by cADP-Ribose in the heart is mediated by enhanced SR Ca2+ uptake into the sarcoplasmic reticulum
AU - Lukyanenko, Valeriy
AU - Györke, Inna
AU - Wiesner, Theodore F.
AU - Györke, Sandor
PY - 2001/9/28
Y1 - 2001/9/28
N2 - 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.
AB - 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.
KW - Ca sparks
KW - Ryanodine receptors
KW - Sarcoplasmic reticulum Ca
KW - Ventricular myocytes
KW - cADP-ribose
UR - http://www.scopus.com/inward/record.url?scp=0035964802&partnerID=8YFLogxK
U2 - 10.1161/hh1901.098066
DO - 10.1161/hh1901.098066
M3 - Article
C2 - 11577027
AN - SCOPUS:0035964802
VL - 89
SP - 614
EP - 622
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 7
ER -