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

Abstract

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 crystallography(7). Available results are consistent with it being a modulator of Ca2+-induced Ca2+ releases(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.