CADP-RIBOSE RELEASES CA2-RETICULUM INDEPENDENTLY OF RYANODINE RECEPTOR( FROM CARDIAC SARCOPLASMIC)

Cyclic ADP-ribose (cADPR), an endogenous metabolite of beta-NAD(+), ac tivates Ca2+ release from endoplasmic reticulum in sea urchin eggs via the ryanodine receptor (RyR) pathway. A similar role has been propose d in cardiac sarcoplasmic reticulum (SR), although this remains contro versial. We therefore investigated the ability of cADPR to induce Ca2 release from canine cardiac SR microsomes using flue 3 to monitor ext ravesicular Ca2+ concentration. We found that cADPR induced Ca2+ relea se in a concentration-dependent manner, whereas neither its precursor, NAD(+),nor its metabolite, ADP-ribose, elicited a consistent effect. In addition, an additive effect on calcium release between cADPR and 9 -Me-7-Br-eudistomin-D (MBED), an activator of RyR, was found as well a s no cross-desensitization between cADPR and MBED. Specific blockers o f the RyR did not abolish the cADPR-induced Ca2+ release. These result s provide evidence for cADPR-induced Ca2+ release from dog cardiac SR via a novel mechanism which is independent of RyR activation.