CYCLIC ADP-RIBOSE AS AN ENDOGENOUS REGULATOR OF THE NONSKELETAL TYPE RYANODINE RECEPTOR CA2+ CHANNEL

THE skeletal and cardiac isoforms1 of the ryanodine receptor Ca2+ channel (RyRC) constitute the Ca2+ release pathway in sarcoplasmic reticulum of skeletal and cardiac muscles, respectively2,3. A direct mechanical and a Ca2+-triggered mechanism (Ca2+-induced Ca2+ release) have been respectively proposed to explain the in situ activation of Ca2+ release in skeletal and cardiac muscle4,5. In non-muscle cells, however, where the RyRC also participates in Ca2+ signalling6-11 the mechanism of RyRC activation is unknown. Cyclic adenosine 5'-diphosphoribose (cADPR)12, which is present in many mammalian tissues13, has been reported to induce Ca2+ release from ryanodine-sensitive intracellular Ca2+ stores in sea urchin eggs14. Here we provide evidence that cADPR directly activates the cardiac but not the skeletal isoform of the RyRC. This, together with results on sea urchin eggs14, suggests that cADPR is an endogenous activator of the non-skeletal type of RyRC and may thus have a role similar to inositol 1,4,5-trisphosphate15 in Ca2+ signalling.