Cyclic ADP ribose activation of the ryanodine receptor is mediated by calmodulin

Cyclic ADP-ribose (cADPR) is a newly identified nucleotide^1,2 which can release calcium from a variety of cells^3-6, suggesting it is a messenger for mobilizing internal Ca²⁺ stores. Its cyclic structure has now been confirmed by X-ray crystallography⁷. Available results are consistent with it being a modulator of Ca²⁺ -induced Ca²⁺ release^8-10. Here we report that sea urchin egg microsomes purified by Percoll gradients lose sensitivity to cADPR, but the response can be restored by a soluble protein in the supernatant. Purification and characterization of the protein indicate that it is calmodulin. It appears to be sensitizing the Ca²⁺ release mechanism because caffeine and strontium, agonists of Ca²⁺ -induced Ca²⁺ release, can also mimic calmodulin in conferring cADPR-sensitivity. Although evidence indicates that cADPR may be an activator of the ryanodine receptor ^8-10, present results point to the importance of accessory proteins such as calmodulin in modulating its activity.