Cyclic ADP-ribose as an endogenous regulator of the non-skeletal type ryanodine receptor Ca²⁺ channel

Abstract

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, respectively ^2,3. 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 muscle^4,5. In non-muscle cells, however, where the RyRC also participates in Ca²⁺ signalling^6–11, 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.