Specific modulation of cyclic ADP-ribose-induced Ca²⁺ release by polyamines

Cyclic ADP-ribose (cADPR) is a potent mediator of Ca²⁺ mobilization from intracellular stores in sea urchin eggs. However, the regulation of the cADPR-induced Ca²⁺ release system is not yet fully elucidated. We now report that spermine and related polyamines, in physiological concentrations, were able to inhibit the Ca²⁺ release induced by cADPR in sea urchin egg homogenate bioassays, as measured using the Ca²⁺ indicator fluo 3, but had no effect on the Ca²⁺ release induced by D-myo-inositol 1,4,5- trisphosphate (IP₃) or by nicotinate adenine dinucleotide phosphate (NAADP). Spermine was a more potent inhibitor of the cADPR-induced Ca²⁺ release than spermidine and putrescine. Spermine inhibited not only the release induced by cADPR but also the Ca²⁺ release induced by caffeine and ryanodine. Finally, pretreatment of the sea urchin egg homogenates with caffeine or Sr²⁺ and Ca²⁺ prevented the inhibitory effect of spermine on cADPR-induced Ca²⁺ release. We propose that polyamines, which are present in millimolar concentrations in fertilized eggs, are specific inhibitors of the ryanodine channel and perhaps may serve as endogenous regulators of the cADPR-induced Ca²⁺ release system.