cADP-ribose releases Ca2+ from cardiac sarcoplasmic reticulum independently of ryanodine receptor.
Cyclic ADP-ribose (cADPR), an endogenous metabolite of beta-NAD+, activates Ca2+ release from endoplasmic reticulum in sea urchin eggs via the ryanodine receptor (RyR) pathway. A similar role has been proposed in cardiac sarcoplasmic reticulum (SR), although this remains controversial. We therefore investigated the ability of cADPR to induce Ca2+ release from canine cardiac SR microsomes using fluo 3 to monitor extravesicular Ca2+ concentration. We found that cADPR induced Ca2+ release 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 as no cross-desensitization between cADPR and MBED. Specific blockers of the RyR did not abolish the cADPR-induced Ca2+ release. These results provide evidence for cADPR-induced Ca2+ release from dog cardiac SR via a novel mechanism which is independent of RyR activation.
Lahouratate
P
P
SmithKline Beecham Laboratoires Pharmaceutiques, Saint-Grégoire, France.
Guibert
J
J
Faivre
J F
JF
D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000494:pharmacology; D000814:Aniline Compounds; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002243:Carbolines / Q000494:pharmacology; D036563:Cyclic ADP-Ribose; D004285:Dogs; D004357:Drug Synergism; D005456:Fluorescent Dyes; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D008955:Models, Cardiovascular; D009124:Muscle Proteins / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D014966:Xanthenes
D000814:Aniline Compounds; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D002243:Carbolines; D005456:Fluorescent Dyes; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D014966:Xanthenes; D009243:NAD; D036563:Cyclic ADP-Ribose; C060741:9-methyl-7-bromoeudistomin D; D000246:Adenosine Diphosphate Ribose; C059715:Fluo-3; D000001:Calcimycin; D002118:Calcium