The cardiac muscle isoform of the ryanodine receptor/Ca2+ release chan
nel (RYR) has been proposed to be an important target of cyclic ADP-ri
bose (cADPR) action in mammalian cells. However, we now demonstrate th
at neither cADPR (0.1-5 mu M), nor the related metabolites beta-NAD(+)
(0.1-30 mM) and ADP-ribose (0.1-5 mu M), affected cardiac RYR activit
y as determined by [SH]ryanodine binding to cardiac sarcoplasmic retic
ulum (SR) vesicles. Similarly, cADPR (1 mu M) failed to activate singl
e cardiac RYR channels in planar lipid bilayers. Skeletal muscle SR [H
-3]ryanodine binding was also unaffected by cADPR (up to 30 mu M). The
se results argue against a direct role for the well-characterized RYRs
of cardiac or skeletal muscle in mediating cADPR-activated Ca2+ relea
se.